Methods and compositions for the prevention and treatment of hearing loss

ABSTRACT

In one aspect, pharmaceutical compositions comprising a CDK2 inhibitor and one or more of at least one agent known to treat a hearing impairment and at least one agent known to prevent a hearing impairment, and methods of treating and/or preventing hearing impairments or disorders using the compositions are disclosed. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/580,224, filed on Dec. 6, 2017, which is a national stage filingunder 35 U.S.C. § 371 of International Application No.PCT/US2016/038384, filed on Jun. 20, 2016, which claims the benefit ofU.S. Provisional Application No. 62/181,755, filed on Jun. 18, 2015, thecontents of which are incorporated herein by reference in theirentireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under grant numbersN00014-09-V-1014, N00014-12-V-0191, N00014-12-V-0775, andN00014-16-V-2315 awarded by the Office of Naval Research, and grantnumbers DC006471, DC013879, and CA021765 awarded by the NationalInstitutes of Health. The government has certain rights in theinvention.

BACKGROUND

Noise-induced hearing loss (NIHL) is the most common sensorineuralhearing impairment. The World Health Organization recently reported thatmore than a billion teens and young adults worldwide are at risk of NIHLcaused by loud music(http://www.cnn.com/2015/03/06/health/hearing-loss-loud-music/index.html).Acute or chronic acoustic overexposure has put more than 40 million U.S.workers at risk of permanent hearing loss (Kopke et al. (2007) Hear.Res. 226: 114-125). NIHL is also prevalent in military settings, costingmore than $2 billion per year in veterans (VA) compensation.

Noise trauma results in two types of hearing loss, depending onintensity and duration: permanent or temporary threshold shift (PTS orTTS). Persons can recover from TTS within 24-48 hrs, whereas PTS isirreversible. Mechanistically, acoustic overexposure causes hearing lossthrough overproduction of reactive oxygen species (ROS), mitochondrialinjury, lipid peroxidation, glutathione (GSH) depletion, reperfusioninjury, excessive glutamate release, and/or loss of hair cells andneurons through programmed cell death (PCD, apoptosis) and inflammatorypathways (Kopke et al. (2007) Hear. Res. 226: 114-125). Many of thesecellular pathways overlap with those involved in hearing loss caused bycisplatin chemotherapy, antibiotics, and age (Mukherjea et al. (2011)Expert Opin. Drug Discov. 6: 491-505; Schacht et al. (2012) Anat. Rec.(Hoboken) 295: 1837-1850; Vu et al. (2013) PLoS One 8: e54794. However,it is not known which pathways, established or novel, are key to theprevention of NIHL and other forms of ototoxicity, such ascisplatin-induced or chemotherapy-induced hearing loss,antibiotic-induced hearing loss, and age-related hearing loss.

Cisplatin is known to exhibit toxic effects on hair cells of the innerear. Indeed, high frequency hearing loss (>8 kHZ) has been reported tobe as high as 90% in children undergoing cisplatin therapy (Allen et al.(1998) Otolaryngol HeadNeck Surg 118: 584-588). Other clinicallyimportant and commonly used drugs also have documented ototoxic effects,including loop diuretics (Greenberg (2000) Am. J. Med. Sci. 319:10-24),antimalarial sesquiterpene lactone endoperoxides (e.g., artemesinins)(Toovey and Jamieson (2004) Trans. R. Soc. Trop. Med. Hyg. 98: 261-267),antimalarial quinines (Claessen et al. (1998) Trop. Med. Int. Health 3:482-489), salicylates (Matz (1990) Ann. Otol. Rhinol. Laryngol. Suppl.148: 39-41), and interferon polypeptides (Formann et al. (2004) Am. J.Gastroenterol. 99: 873-877).

Moreover, ototoxicity to the vestibular system, which includes thevestibule and semicircular canal, manifests as balance andorientation-related disorders. These disorders include, but are notlimited to, induced or spontaneous vertigo, dysequilibrium, increasedsusceptibility to motion sickness, nausea, vomiting, ataxia,labyrinthitis, oscillopsia, nystagmus, syncope, lightheadedness,dizziness, increased falling, difficulty walking at night, Meniere'sdisease, and difficulty in visual tracking and processing.

Extensive research in recent years has sought to identify smallmolecules that can protect against hearing loss. Those tested can beclassified into three different groups based on their main cellularfunction: 1) antioxidants and ROS scavengers, 2) anti-inflammatorydrugs, and 3) apoptosis inhibitors. Many candidate compounds arecurrently in pre-clinical and clinical trials; most are related toantioxidants, vitamins, and glutathione metabolism, although theireffectiveness remains unclear.

Despite the promising protective effects of N-acetylcysteine (NAC) inpreclinical and clinical safety studies, it has shown no protectionagainst NIHL in several clinical trials (Kopke et al. (2007) Hear. Res.226: 114-125; Tieu and Campbell (2013) Otolaryngology 3:130).D-methionine has shown protective effects against NIHL but remains to betested in clinical trials (Muller and Barr-Gillespie (2015) Nat. Rev.Drug Discov. 14: 346-365; Oishi and Schacht (2011) Expert Opin. Emerg.Drugs 16: 235-245). Similarly, Ebelsen (SPI-1005), a seleno-organiccompound with antioxidant activity through glutathione peroxidase-likeaction, has been tested against TTS in noise-induced excitotoxicitystudies but remains unproven in clinical trials (See “SoundPharmaceuticals Inc. successfully completes its first Phase 2 clinicaltrial with SPI-1005” (Nov. 5, 2013); Lynch and Kil (2005) Drug Discov.Today 10: 1291-1298). To date, no drugs are FDA-approved for protectionagainst NIHL and traumatic brain injury (TBI)-associated hearing loss.Thus, there remains a need for compositions and methods of preventingand treating hearing loss.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompositions and methods for use in the prevention and treatment of ahearing impairment.

Disclosed are methods of treating hearing impairment, the methodscomprising administering to a subject diagnosed with a need fortreatment of hearing impairment a therapeutically effective amount of acyclin-dependent kinase 2 (CDK2) inhibitor, or a pharmaceuticallyacceptable salt thereof.

Also disclosed are methods of preventing hearing impairment, the methodscomprising administering to a subject a CDK2 inhibitor in an amount offrom about 0.001 μM to about 1.0×10⁴ μM at least once every three weeks,or a pharmaceutically acceptable salt thereof.

Also disclosed are pharmaceutical compositions comprising a CDK2inhibitor, or a pharmaceutically acceptable salt thereof; and one ormore of: (a) at least one agent known to treat hearing impairment, or apharmaceutically acceptable salt thereof; and (b) at least one agentknown to prevent hearing impairment, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier.

Also disclosed are pharmaceutical compositions comprising a CDK2inhibitor, wherein the CDK2 inhibitor is not a paullone derivative, or apharmaceutically acceptable salt thereof; and one or more of: at leastone agent known to treat hearing impairment, or a pharmaceuticallyacceptable salt thereof; and at least one agent known to prevent hearingimpairment, or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.

Also disclosed are methods for making compounds and for making compoundsfor use in pharmaceutical compositions. Also disclosed are the productsof said methods.

Also disclosed are methods of preparing a pharmaceutical composition,the method comprising the step of combining a CDK2 inhibitor, or apharmaceutically acceptable salt thereof; and one or more of: (a) atleast one agent known to treat hearing impairment, or a pharmaceuticallyacceptable salt thereof; (b) at least one agent known to prevent hearingimpairment, or a pharmaceutically acceptable salt thereof, wherein atleast one is present in an effective amount; and a pharmaceuticallyacceptable carrier.

Also disclosed are kits comprising a CDK2 inhibitor, or apharmaceutically acceptable salt thereof; and one or more of: (a) atleast one agent known to treat a hearing impairment; (b) at least oneagent known to prevent a hearing impairment; (c) at least one antibioticagent; (d) at least one chemotherapeutic agent; (e) instructions fortreating a hearing impairment; and (f) instructions for preventing ahearing impairment.

Also disclosed are kits comprising a compound selected from:

or a pharmaceutically acceptable salt thereof; and one or more of: (a)at least one agent known to treat a hearing impairment; (b) at least oneagent known to prevent a hearing impairment; (c) at least one antibioticagent; (d) at least one chemotherapeutic agent; (e) instructions fortreating a hearing impairment; and (f) instructions for preventing ahearing impairment.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows a representative plot illustrating the percent activity ofthe bioactive compounds in a cell-based high-throughput screen.

FIG. 2a-e show representative dose response curves of kenpaullone(compound 4) (FIG. 2a ), Olomoucine II (compound 9) (FIG. 2b ), CDK2inhibitor II (compound 12) (FIG. 2c ), compound 3 (FIG. 2d ), andcompound 1 (FIG. 2e ), determined using the Caspase-/37 Glo assay andthe Promega Cell Titer Glo assay (CTG).

FIG. 3A-G show representative data illustrating that compounds 4 (FIG.3A-E), 9 (olomoucine II or compound 9, FIG. 3F), and 12 (CDK2 inhibitorII or compound 12, FIG. 3G) protect against cisplatin-induced hair cellloss in cochlear explants.

FIG. 4A-E show representative data illustrating that compound 4 protectsagainst cisplatin-induced hair cell loss in zebrafish lateral lines invivo.

FIG. 5 shows kenpaullone protects against cisplatin-induced hair cellloss in vivo in mouse. Panel 5 a shows experimental diagram. Either earof the same FVB wild-type mouse at P28 was trans-tympanically injected(in a volume of 5 μL) with compound (Kenpaullone 250 μM in 0.5% DMSO) or0.5% DMSO only, in a double-blinded manner. Two hours later, the micewere treated intraperitoneally (IP) with cisplatin 30 mg/kg body weight,which was expected to damage OHCs equally in both ears. Panel 5 bdemonstrates that kenpaullone (Ken) significantly reduces cisplatin(Cis)-induced ABR hearing threshold shifts relative to DMSO control at16 kHz and 32 kHz 14 days post transtympanic injection. Panel 5 c showsrepresentative images double stained with phalloidin and myosin 7a whichis a hair cell specific marker in the cochlea and illustrates thatkenpaullone protects against cisplatin-induced hair cell loss at 32 kHzregion 14 days post transtympanic injection. Panel 5 d demonstrateskenpaullone significantly increases outer hair cell (OHC) survival inall 11 mice at the 32 kHz region.

FIG. 6 shows kenpaullone protects against noise-induced hearing loss.Panel 6 a is an experimental design in which adult FVB mice at P28 wereexposed to noise (8-16 kHz at 100 dB SPL for 2 hours). Immediatelyafterward, kenpaullone (250 μM in 0.5% DMSO) or 0.5% DMSO was delivered(via trans-tympanic injection) to either ear of the same mouse. ABRthresholds were recorded prior, 7 days, or 14 days post noise exposure.Cochlear histology was examined at 14 days. Panel 6 b shows that, in atotal of 19 mice, kenpaullone significantly protects noise-inducedhearing loss at 8 kHz and 16 kHz 14 days post noise damage. Panel 6 calso shows that wave 1 amplitudes of ABRs at 16 kHz displayedsignificant differences between the kenpaullone and DMSO control ears.Panel 6 d shows representative images of triple staining withphalloidin, Tuj1 and myosin 7a in the organ of Corti. There are no haircell loss and no detectable spiral ganglion neuron fiber differences atthe 16 kHz region. Panel 6 e comparison of the ctbp2 puncta staining andqualification in control (Ctrl) without any treatment, noise damage withDMSO transtympanic injection (DMSO+Noise) and noise damage withkenpaullone transtympanic injection (Ken+Noise). Kenpaullonesignificantly protects ctbp2 puncta loss comparing with DMSO sample.Inner hair cells (IHCs) are traced by dash line in Panel 6 e top figure.

FIG. 7 shows kenpaullone inhibits CDK2 kinase activity in vitro.Increasing doses of kenpaullone were tested with Cdk2 immunoprecipitatedfrom HEI-OC cells without (panel 7 a) or with (panel 7 b) cisplatintreatment and the kinase activity was quantified as the level ofphosphorylation of the substrate histone H1. Three (N=3) independentexperiments were used for calculation of IC₅₀.

FIG. 8 shows germline CDK2 knockout (KO) cochlear explants conferresistance to cisplatin treatment and kenpaullone administrationphenocopies CDK2 knockout resistance to cisplatin ototoxicity. Panels 8a-c show middle turn organs of Corti with actin staining(phalloidin-Alexa Flour 568) in WT and CDK2 KO cochleae without anytreatment (Media, panel 8 a), with 50 M cisplatin treatment (panel 8 b)and with 50 M cisplatin and 5 M kenpaullone (Panel 8 c). Outer hair cell(OHCs) numbers of actin-positive cells per 160 μm of the middle turncochleae were counted (panel 8 d) and data are mean±s.e.m. Numbers ofexplants tested in each condition are indicated in the bars. *** P<0.001by one-way ANOVA with Bonferroni's multiple comparison test.

FIG. 9 shows testing of kenpaullone toxicity in vivo in adult FVB mice(˜P28). FVB mice at P28 were administrated kenpaullone at variousconcentrations (310 μM, 155 μM and 77.5 μM) by transtympanic injection.Basel turn organs of Corti 24 hours post kenpaullone treatments asvisualized by DAPI and Parvalbumin show that kenpaullone is toxic at 310μM but not at lower doses. Arrows label lost outer hair cells. Twoindependent mice were tested for each dose.

FIG. 10 shows the lack of toxicity of kenpaullone (at 250 μM bytranstymapnic injection) in vivo. Panel 10 a shows no significant ABRthreshold shifts 7 days, 14 days, 28 days, 56 days and 84 days postkenpaullone or DMSO transtympanic injection at 16 kHz. Panel 10 bdemonstrates there are no detectable ABR threshold shifts 84 days postkenpaullone or DMSO transtympanic injection at 8 kHz, 16 kHz and 32 kHz.Panel 10 c indicates kenpaullone treatment does not affect the length ofthe cochlea. Panel 10 d visualizes organs of Corti 84 days postkenpaullone (Ken) treatment in vivo and demonstrates that kenpaullonelacks ototoxicity at 250 μM after 84 days in vivo.

FIG. 11 addresses interference with cisplatin's killing function intumors. Four neurosphere lines derived from mouse medulloblastoma (MB)and two human neuroblastoma (NB) cell lines were tested. HEI-OC1 cellline was tested as controls. Viability assay (Cell Titer Glo) was used48 hours post treatment of the cells with or without cisplatin (23 μM,IC_(90±10) for all 7 cell lines) and each tested compound (conc. of3×IC₅₀). * and ** indicated p<0.05 and 0.01 respectively.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

As used in the specification and in the claims, the term “comprising”can include the aspects “consisting of” and “consisting essentially of.”

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

As used herein, the terms “about” and “at or about” mean that the amountor value in question can be the value designated some other valueapproximately or about the same. It is generally understood, as usedherein, that it is the nominal value indicated ±10% variation unlessotherwise indicated or inferred. The term is intended to convey thatsimilar values promote equivalent results or effects recited in theclaims. That is, it is understood that amounts, sizes, formulations,parameters, and other quantities and characteristics are not and neednot be exact, but can be approximate and/or larger or smaller, asdesired, reflecting tolerances, conversion factors, rounding off,measurement error and the like, and other factors known to those ofskill in the art. In general, an amount, size, formulation, parameter orother quantity or characteristic is “about” or “approximate” whether ornot expressly stated to be such. It is understood that where “about” isused before a quantitative value, the parameter also includes thespecific quantitative value itself, unless specifically statedotherwise.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side effects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “dosage form” means a pharmacologically active materialin a medium, carrier, vehicle, or device suitable for administration toa subject. A dosage forms can comprise inventive a disclosed compound, aproduct of a disclosed method of making, or a salt, solvate, orpolymorph thereof, in combination with a pharmaceutically acceptableexcipient, such as a preservative, buffer, saline, or phosphate bufferedsaline. Dosage forms can be made using conventional pharmaceuticalmanufacturing and compounding techniques. Dosage forms can compriseinorganic or organic buffers (e.g., sodium or potassium salts ofphosphate, carbonate, acetate, or citrate) and pH adjustment agents(e.g., hydrochloric acid, sodium or potassium hydroxide, salts ofcitrate or acetate, amino acids and their salts) antioxidants (e.g.,ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20,polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate),solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol,trehalose), osmotic adjustment agents (e.g., salts or sugars),antibacterial agents (e.g., benzoic acid, phenol, gentamicin),antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g.,thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers andviscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488,carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethyleneglycol, ethanol). A dosage form formulated for injectable use can have adisclosed compound, a product of a disclosed method of making, or asalt, solvate, or polymorph thereof, suspended in sterile salinesolution for injection together with a preservative.

As used herein, “kit” means a collection of at least two componentsconstituting the kit. Together, the components constitute a functionalunit for a given purpose. Individual member components may be physicallypackaged together or separately. For example, a kit comprising aninstruction for using the kit may or may not physically include theinstruction with other individual member components. Instead, theinstruction can be supplied as a separate member component, either in apaper form or an electronic form which may be supplied on computerreadable memory device or downloaded from an internet website, or asrecorded presentation.

As used herein, “instruction(s)” means documents describing relevantmaterials or methodologies pertaining to a kit. These materials mayinclude any combination of the following: background information, listof components and their availability information (purchase information,etc.), brief or detailed protocols for using the kit, trouble-shooting,references, technical support, and any other related documents.Instructions can be supplied with the kit or as a separate membercomponent, either as a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from aninternet website, or as recorded presentation. Instructions can compriseone or multiple documents, and are meant to include future updates.

As used herein, the term “CDK2 Inhibitor” refers to a small moleculechemical compound that binds to CDK2 protein isolated from cochlearcells and cochlear explants, inhibits CDK2 kinase or other activitieswith IC₅₀ of <10 μM, and thus prevents cisplatin-induced hair cell losswith IC₅₀ of <10 μM. See FIGS. 3, 7, and 8.

As used herein, the term “therapeutic agent” includes any synthetic ornaturally occurring biologically active compound or composition ofmatter which, when administered to an organism (human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, vaccines, and biopharmaceuticals including molecules such asproteins, peptides, hormones, nucleic acids, gene constructs and thelike. Examples of therapeutic agents are described in well-knownliterature references such as the Merck Index (14^(th) edition), thePhysicians' Desk Reference (64^(th) edition), and The PharmacologicalBasis of Therapeutics (12^(th) edition), and they include, withoutlimitation, medicaments; vitamins; mineral supplements; substances usedfor the treatment, prevention, diagnosis, cure or mitigation of adisease or illness; substances that affect the structure or function ofthe body, or pro-drugs, which become biologically active or more activeafter they have been placed in a physiological environment. For example,the term “therapeutic agent” includes compounds or compositions for usein all of the major therapeutic areas including, but not limited to,adjuvants; anti-infectives such as antibiotics and antiviral agents;analgesics and analgesic combinations, anorexics, anti-inflammatoryagents, anti-epileptics, local and general anesthetics, hypnotics,sedatives, antipsychotic agents, neuroleptic agents, antidepressants,anxiolytics, antagonists, neuron blocking agents, anticholinergic andcholinomimetic agents, antimuscarinic and muscarinic agents,antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, andnutrients, antiarthritics, antiasthmatic agents, anticonvulsants,antihistamines, antinauseants, antineoplastics, antipruritics,antipyretics; antispasmodics, cardiovascular preparations (includingcalcium channel blockers, beta-blockers, beta-agonists andantiarrythmics), antihypertensives, diuretics, vasodilators; centralnervous system stimulants; cough and cold preparations; decongestants;diagnostics; hormones; bone growth stimulants and bone resorptioninhibitors; immunosuppressives; muscle relaxants; psychostimulants;sedatives; tranquilizers; proteins, peptides, and fragments thereof(whether naturally occurring, chemically synthesized or recombinantlyproduced); and nucleic acid molecules (polymeric forms of two or morenucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA)including both double- and single-stranded molecules, gene constructs,expression vectors, antisense molecules and the like), small molecules(e.g., doxorubicin) and other biologically active macromolecules suchas, for example, proteins and enzymes. The agent may be a biologicallyactive agent used in medical, including veterinary, applications and inagriculture, such as with plants, as well as other areas. The term“therapeutic agent” also includes without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of disease or illness; orsubstances which affect the structure or function of the body; orpro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

The term “hearing impairment” as used herein refers to a neurologicdisorder, oto-neurological in nature, typically sensorineural, butincluding composite loss (both sensorineural and conductive loss),preferably either a sensory or a neural (8^(th) nerve related) hearinglost, and most preferably a sensory loss (cochlear related), in whichthe patient will display, complain of, or is diagnosed to have a hearingloss. Conductive hearing loss is typically related to the external ormiddle ear. These impairments of interest to the present invention arethose associated with hair cell damage. Less preferably such impairmentscan occur along with conductive hearing loss damage or damage, loss, ordegeneration of a neuron of the auditory system. Hair cells areepithelial cells possessing fine projections and located in the maculaeand the organ of Corti.

Examples of hearing impairments and situations in which such hearingimpairments can occur encompassed by the term “hearing impairment,” asused herein, include sensory hearing loss due to end-organ lesions,e.g., acoustic trauma, viral endolymphatic labyrinthitis, and Meniere'sdisease. The impairment can also be a neural hearing loss due to eventsincluding cerebellopontine angle tumors of the 8^(th) nerve. Hearingimpairments include tinnitus, this is a perception of sound in theabsence of an acoustic stimulus, and may be intermittent or continuous,wherein there is a diagnosed sensorineural loss. Hearing loss may be dueto bacterial or viral infection of the 8^(th) nerve ganglia, such as inherpes zoster oticus, purulent labyrinthitis arising from acute otitismedia, purulent meningitis, chronic otitis media, sudden deafnessincluding that of viral origin, e.g., viral endolymphatic labyrinthitiscaused by viruses including mumps, measles, influenza, chickenpox,mononucleosis, and adenoviruses. The hearing loss can be congenital,such as that caused by rubella, anoxia during birth, bleeding into theinner ear due to trauma during delivery, ototoxic drugs administered tothe mother, erythroblastosis fetalis, and hereditary conditionsincluding Waardenburg's syndrome and Hurler's syndrome. The hearing losscan be noise-induced, generally due to a noise greater than 85 decibels(db) SPL (sound pressure level) that damages the inner ear. Hearing lossincludes presbycusis, which is a sensorineural hearing loss occurring asa normal part of aging, fractures of the temporal bone extending intothe middle ear and rupturing the tympanic membrane and possibly theossicular chain, fractures affecting the cochlea, and acousticneurinoma, which are tumors generally of Shwann cell origin that arisefrom either the auditory or vestibular divisions of the 8^(th) nerve. Invarious aspects, the hearing loss is caused by an ototoxic drug thataffects the auditory portion of the inner ear, particularly the organ ofCorti. The hearing loss may be due to chemotherapy or to cisplatin. Thehearing loss can be related to a vestibular disorder including vertigo,dysequilibrium, increased susceptibility to motion sickness, nausea,vomiting, ataxia, labyrinthitis, oscillopsia, nystagmus, syncope,lightheadedness, dizziness, increased falling, difficulty walking atnight, Meniere's disease, and difficulty in visual tracking andprocessing. Incorporated herein by reference are Chapters 196, 197, 198,and 199 of The Merck Index, 14^(th) Edition (1982), Merck Sharp & DomeResearch Laboratories, N.J. and related chapters in the most recentedition, relating to description and diagnosis of hearing impairments.

Tests are known and available for diagnosing hearing impairments.Neuro-otological, neuro-ophthalmological, neurological examinations, andelectra-oculography can be used (Wennmo et al., Acta Otolaryngol 1982,94, 507). Sensitive and specific measures are available to identifypatients with auditory impairments. For example, tuning fork tests canbe used to differentiate a conductive from a sensorineural hearing lossand determine whether the loss is unilateral. An audiometer is used toquantitate hearing loss, measured in decibels. With this device thehearing for each ear is measured, typically from 125 to 8000 Hz, andplotted as an audiogram. Speech audiometry can also be performed. Thespeech recognition threshold, the intensity at which speed is recognizedas a meaningful symbol, can be determined at various speech frequencies.Speech or phoneme discrimination can also be determined and used as anindicator of sensorineural hearing loss since analysis of speech soundsrelies upon the inner ear and 8^(th) nerve. Tympanometry can be used todiagnose conductive hearing loss and aid in the diagnosis of thosepatients with sensorineural hearing loss. Electrocochleography,measuring the cochlear microphonic response and action potential of the8^(th) nerve, and evoked response audiometry, measuring evoked responsefrom the brainstem and auditory cortex, to acoustic stimuli can be usedin patients, particularly infants and children or patients withsensorineural hearing loss of obscure etiology. Auditory brainstemresponses (ABRs) or distortion products otoacoustic emissions (DPOAEs)are most commonly used audiometry methods. These tests serve adiagnostic function as well as a clinical function in assessing responseto therapy.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms. The term alkyl group can also bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the likeup to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbomyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbomenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the it clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl can be two aryl groups that arebound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen,” or “halide,” as used herein can be usedinterchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl,” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quatemized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl,” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The terms “heterocycle” or “heterocyclyl,” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic ornon-aromatic ring systems in which at least one of the ring members isother than carbon. Thus, the term is inclusive of, but not limited to,“heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclicheterocycle.” Heterocycle includes pyridine, pyrimidine, furan,thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole,imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole,1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including,1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazoleand 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. Theterm heterocyclyl group can also be a C2 heterocyclyl, C2-C3heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like upto and including a C2-C18 heterocyclyl. For example, a C2 heterocyclylcomprises a group which has two carbon atoms and at least oneheteroatom, including, but not limited to, aziridinyl, diazetidinyl,dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, forexample, a C5 heterocyclyl comprises a group which has five carbon atomsand at least one heteroatom, including, but not limited to, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and thelike. It is understood that a heterocyclyl group may be bound eitherthrough a heteroatom in the ring, where chemically possible, or one ofcarbons comprising the heterocyclyl ring.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as usedherein refers to a ring system in which at least one of the ring membersis other than carbon. Bicyclic heterocyclyl encompasses ring systemswherein an aromatic ring is fused with another aromatic ring, or whereinan aromatic ring is fused with a non-aromatic ring. Bicyclicheterocyclyl encompasses ring systems wherein a benzene ring is fused toa 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms orwherein a pyridine ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, butare not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems. The heterocycloalkyl ring-systems include one to fourheteroatoms independently selected from oxygen, nitrogen, and sulfur,wherein a nitrogen and sulfur heteroatom optionally can be oxidized anda nitrogen heteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited to, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxyl” or “hydroxyl” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogen of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄R^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R)C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R; —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(S)NR^(∘) ₂; —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR)R^(∘);—C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R; —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R;—N(OR)R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘) ₂;—OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(●) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(∘), -(haloR^(∘)), —OH, —OR^(∘), —O(haloR^(∘)), —CN, —C(O)OH,—C(O)OR^(∘), —NH₂, —NHR^(∘), —NR^(∘) ₂, or —NO₂, wherein each R^(∘) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(∘), -(haloR^(∘)), —OH, —OR^(∘), —O(haloR^(∘)), —CN,—C(O)OH, —C(O)OR^(∘), —NH₂, —NHR^(∘), —NR^(∘) ₂, or —NO₂, wherein eachR^(∘) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, and brosylate.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the Compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and l or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Ingold-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labeled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et. al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. As another example, pyrazoles canexist in two tautomeric forms, N¹-unsubstituted, 3-A³ andN¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possibletautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n)(a) is halogen, then R^(n)(b) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andsupplemental volumes (Elsevier Science Publishers, 1989); OrganicReactions, Volumes 1-40 (John Wiley and Sons, 1991); March's AdvancedOrganic Chemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B—F, C-D, C-E, and C—F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Compounds

In one aspect, disclosed are compounds useful in treating or preventinghearing disorders. In a further aspect, the disclosed compounds exhibitinhibition of CDK2. In a still further aspect, the disclosed compoundsexhibit antagonism of CDK2.

In one aspect, the compounds of the invention are useful in thetreatment or prevention of hearing disorders associated with CDK2dysfunction and other diseases in which CDK2s are involved, as furtherdescribed herein.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Paullone Derivatives

In various aspects, the compound is a paullone derivative, or apharmaceutically acceptable solvate, salt, or polymorph thereof.Paullones are a family of benzazepinones characterized by a coreframework represented by a structure:

Paullones constitute a well-established class of cyclin-dependent kinase(CDK) inhibitors. CDK's are a family of serine/threonine protein kinasesknown to play a central role in the normal growth and life cycle ofeukaryotic cells. Inhibitors of CDK could potentially serve aspharmacological agents to treat diseases of proliferation such ascancer, psoriasis, and restenosis (Sharma, V. M., et al. (2008) IndianJ. of Biochem. & Biophysics 45, 416; Leost, M., et al. (2000) Eur. J.Biochem. 267, 5983-5994).

Paullone derivatives have been previously described in, for example, US2003/0181439 A1; U.S. Pat. No. 7,232,814 B2; Kunick, C., et al. (2005)ChemBioChem 6, 541-549; Zaharevitz, D., et al. (1999) Cancer Res. 59,2566-2569; Leost, M., et al. (2000) Eur. J Biochem. 267, 5983-5994; WO2006/117212 A2; WO 2009/010298 A2; Sharma, V. M., et al. (2008) IndianJ. of Biochem. & Biophysics 45, 416; Pies, T. (2003) Dissertation,Hamburg University, Hamburg, GER, which are herein incorporated byreference.

In one aspect, disclosed are paullone derivatives having a structurerepresented by a formula:

wherein R¹ is selected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂,—(S═O)R³, —SO₂R₃, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl,C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl,C1-C6 monoalkylamino, and C1-C6 dialkylamino; wherein R³, when present,is selected from hydrogen, —CH₃, —CFH₂, —CF₂H, —CF₃, —NH₂, —NH(CH₃), and—N(CH₃)₂; wherein R² is selected from hydrogen, halogen, —OH, —CN, —NO₂,—NH₂, —(S═O)R⁴, —SO₂R₄, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino; and whereinR⁴, when present, is selected from hydrogen, —CH₃, —CFH₂, —CF₂H, —CF₃,—NH₂, —NH(CH₃), and —N(CH₃)₂, or a pharmaceutically acceptable saltthereof.

In a further aspect, the paullone derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the paullone derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the paullone derivative has a structure representedby a formula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the paullone derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the paullone derivative has a structure representedby a formula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the paullone derivative has a structure representedby a formula:

or a pharmaceutically acceptable salt thereof.

a. R¹ Groups

In one aspect, R¹ is selected from hydrogen, halogen, —OH, —CN, —NO₂,—NH₂, —(S═O)R³, —SO₂R₃, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino. In a furtheraspect, R¹ is selected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂,—(S═O)R³, —SO₂R₃, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl,C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl,C1-C3 monoalkylamino, and C1-C3 dialkylamino.

In a further aspect, R¹ is selected from hydrogen, halogen, —OH, —CN,—NO₂, —NH₂, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6monoalkylamino, and C1-C6 dialkylamino. In a still further aspect, R¹ isselected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂, C1-C3 alkyl,C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino,and C1-C3 dialkylamino. In yet a further aspect, R¹ is selected fromhydrogen, —F, —Cl, —Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃,—OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R¹ is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino,and C1-C6 dialkylamino. In a still further aspect, R¹ is selected fromhydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3 dialkylamino. In yet afurther aspect, R¹ is selected from hydrogen, —F, —Cl, —Br, —CH₃, —CFH₂,—CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R¹ is selected from hydrogen, C1-C6 monohaloalkyl,and C1-C6 polyhaloalkyl. In a still further aspect, R¹ is selected fromhydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In yet a furtheraspect, R¹ is selected from hydrogen, —CClH₂, —CCl₂H, —CCl₃, —CFH₂,—CF₂H, and —CF₃. In an even further aspect, R¹ is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R¹ is selected from hydrogen and C1-C6 alkyl. In astill further aspect, R¹ is selected from hydrogen, methyl, ethyl,iso-propyl, n-propyl, tert-butyl, sec-butyl, iso-butyl, and n-butyl. Inyet a further aspect, R¹ is selected from hydrogen, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, R¹ is selected fromhydrogen, methyl, and ethyl. In a still further aspect, R¹ is selectedfrom hydrogen and methyl. In yet a further aspect, R¹ is selected fromhydrogen and ethyl. In an even further aspect, R¹ is hydrogen. In astill further aspect, R¹ is methyl. In yet a further aspect, R¹ isethyl.

In a further aspect, R¹ is selected from hydrogen and halogen. In astill further aspect, R¹ is selected from hydrogen, —F, —Cl, and —Br. Inyet a further aspect, R¹ is selected from hydrogen, —F, and —Cl. In aneven further aspect, R¹ is selected from hydrogen and —F. In a stillfurther aspect, R¹ is selected from hydrogen and —Cl.

In a further aspect, R¹ is halogen. In a still further aspect, R¹ isselected from —F, —Cl, and —Br. In yet a further aspect, R¹ is selectedfrom —F and —Cl. In an even further aspect, R¹ is —Br. In a stillfurther aspect, R¹ is —Cl. In yet a further aspect, R¹ is —F.

b. R² Groups

In one aspect, R² is selected from hydrogen, halogen, —OH, —CN, —NO₂,—NH₂, —(S═O)R⁴, —SO₂R₄, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6monoalkylamino, and C1-C6 dialkylamino. In a further aspect, R² isselected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂, —(S═O)R⁴, —SO₂R₄,C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino,and C1-C3 dialkylamino.

In a further aspect, R² is selected from hydrogen, halogen, —OH, —CN,—NO₂, —NH₂, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6monoalkylamino, and C1-C6 dialkylamino. In a still further aspect, R² isselected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂, C1-C3 alkyl,C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino,and C1-C3 dialkylamino. In yet a further aspect, R² is selected fromhydrogen, —F, —Cl, —Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃,—OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R² is selected from hydrogen, halogen, C1-C6 alkyl,C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino,and C1-C6 dialkylamino. In a still further aspect, R² is selected fromhydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3 dialkylamino. In yet afurther aspect, R² is selected from hydrogen, —F, —Cl, —Br, —CH₃, —CFH₂,—CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R² is selected from hydrogen, C1-C6 monohaloalkyl,and C1-C6 polyhaloalkyl. In a still further aspect, R² is selected fromhydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In yet a furtheraspect, R² is selected from hydrogen, —CClH₂, —CCl₂H, —CCl₃, —CFH₂,—CF₂H, and —CF₃. In an even further aspect, R² is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R² is selected from hydrogen and C1-C6 alkyl. In astill further aspect, R² is selected from hydrogen, methyl, ethyl,iso-propyl, n-propyl, tert-butyl, sec-butyl, iso-butyl, and n-butyl. Inyet a further aspect, R² is selected from hydrogen, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, R² is selected fromhydrogen, methyl, and ethyl. In a still further aspect, R² is selectedfrom hydrogen and methyl. In yet a further aspect, R² is selected fromhydrogen and ethyl. In an even further aspect, R² is hydrogen. In astill further aspect, R² is methyl. In yet a further aspect, R² isethyl.

In a further aspect, R² is selected from hydrogen and halogen. In astill further aspect, R² is selected from hydrogen, —F, —Cl, and —Br. Inyet a further aspect, R² is selected from hydrogen, —F, and —Cl. In aneven further aspect, R² is selected from hydrogen and —F. In a stillfurther aspect, R² is selected from hydrogen and —Cl.

In a further aspect, R² is halogen. In a still further aspect, R² isselected from —F, —Cl, and —Br. In yet a further aspect, R² is selectedfrom —F and —Cl. In an even further aspect, R² is —Br. In a stillfurther aspect, R² is —Cl. In yet a further aspect, R² is —F.

c. R³ Groups

In one aspect, R³, when present, is selected from hydrogen, —CH₃, —CFH₂,—CF₂H, —CF₃, —NH₂, —NH(CH₃), and —N(CH₃)₂. In a further aspect, R³, whenpresent, is selected from hydrogen, —CH₃, —CFH₂, —CF₂H, —NH₂, —NH(CH₃),and —N(CH₃)₂. In a still further aspect, R³, when present, is selectedfrom hydrogen, —CH₃, —CFH₂, —NH₂, and —NH(CH₃). In yet a further aspect,R³, when present, is selected from hydrogen, —CH₃, and —NH₂. In an evenfurther aspect, R³, when present, is selected from hydrogen and —CH₃. Ina still further aspect, R³, when present, is selected from hydrogen and—NH₂. In yet a further aspect, R³, when present, is hydrogen.

d. R⁴ Groups

In one aspect, R⁴, when present, is selected from hydrogen, —CH₃, —CFH₂,—CF₂H, —CF₃, —NH₂, —NH(CH₃), and —N(CH₃)₂. In a further aspect, R⁴, whenpresent, is selected from hydrogen, —CH₃, —CFH₂, —CF₂H, —NH₂, —NH(CH₃),and —N(CH₃)₂. In a still further aspect, R⁴, when present, is selectedfrom hydrogen, —CH₃, —CFH₂, —NH₂, and —NH(CH₃). In yet a further aspect,R⁴, when present, is selected from hydrogen, —CH₃, and —NH₂. In an evenfurther aspect, R⁴, when present, is selected from hydrogen and —CH₃. Ina still further aspect, R⁴, when present, is selected from hydrogen and—NH₂. In yet a further aspect, R⁴, when present, is hydrogen.

2. Purine Derivatives

In one aspect, disclosed are purine derivatives having a structurerepresented by a formula:

wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C8 alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and wherein eachof R^(5a) and R^(5b) is independently substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl; wherein q, when present, is an integer selected from1, 2, 3, and 4; wherein R⁸, when present, is selected from hydrogen,—OH, —SH, —NH₂, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, andC1-C4 dialkylamino; wherein R⁶ is selected from halogen, OR⁹, andNR^(10a)R^(10b); wherein R⁹, when present, is selected from C1-C8 alkyl,(CH₂)_(p)Cy¹, and (CH₂)_(p)Ar¹ and wherein R⁹, when present, issubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl; wherein p, when present,is an integer selected from 0, 1, 2, and 3; wherein Cy¹, when present,is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;wherein Ar¹, when present, is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;wherein each of R^(10a) and R^(10b), when present, is independentlyselected from C1-C8 alkyl, Cy², Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² andsubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl; wherein r, when present,is an integer selected from 0, 1, 2, and 3; wherein Cy², when present,is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;wherein Ar², when present, is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; andwherein R⁷, when present, is selected from hydrogen and C1-C8 alkyl, ora pharmaceutically acceptable salt thereof.

In one aspect, q, when present, is an integer selected from 1, 2, 3, and4. In a further aspect, q, when present, is an integer selected from 1,2, and 3. In a still further aspect, q, when present, is an integerselected from 2, 3, and 4. In yet a further aspect, q, when present, isan integer selected from 1, 2, and 4. In an even further aspect, q, whenpresent, is an integer selected from 1, 3, and 4. In a still furtheraspect, q, when present, is an integer selected from 1 and 2. In yet afurther aspect, q, when present, is an integer selected from 1 and 3. Inan even further aspect, q, when present, is an integer selected from 1and 4. In a still further aspect, q, when present, is an integerselected from 2 and 3. In yet a further aspect, q, when present, is aninteger selected from 2 and 4. In an even further aspect, q, whenpresent, is an integer selected from 3 and 4. In a still further aspect,q, when present, is 1. In yet a further aspect, q, when present, is 2.In an even further aspect, q, when present, is 3. In a still furtheraspect, q, when present, is 4.

In one aspect, p, when present, is an integer selected from 0, 1, 2, and3. In a further aspect, p, when present, is an integer selected from 0,1, and 2. In a still further aspect, p, when present, is an integerselected from 0, 1, and 3. In yet a further aspect, p, when present, isan integer selected from 0, 2, and 3. In an even further aspect, p, whenpresent, is an integer selected from 1, 2, and 3. In a still furtheraspect, p, when present, is an integer selected from 0 and 1. In yet afurther aspect, p, when present, is an integer selected from 0 and 2. Inan even further aspect, p, when present, is an integer selected from 0and 3. In a still further aspect, p, when present, is an integerselected from 1 and 2. In yet a further aspect, p, when present, is aninteger selected from 1 and 3. In an even further aspect, p, whenpresent, is an integer selected from 2 and 3. In a still further aspect,p, when present, is 0. In yet a further aspect, p, when present, is 1.In an even further aspect, p, when present, is 2. In a still furtheraspect, p, when present, is 3.

In one aspect, r, when present, is an integer selected from 0, 1, 2, and3. In a further aspect, r, when present, is an integer selected from 0,1, and 2. In a still further aspect, r, when present, is an integerselected from 0, 1, and 3. In yet a further aspect, r, when present, isan integer selected from 0, 2, and 3. In an even further aspect, r, whenpresent, is an integer selected from 1, 2, and 3. In a still furtheraspect, r, when present, is an integer selected from 0 and 1. In yet afurther aspect, r, when present, is an integer selected from 0 and 2. Inan even further aspect, r, when present, is an integer selected from 0and 3. In a still further aspect, r, when present, is an integerselected from 1 and 2. In yet a further aspect, r, when present, is aninteger selected from 1 and 3. In an even further aspect, r, whenpresent, is an integer selected from 2 and 3. In a still further aspect,r, when present, is 0. In yet a further aspect, r, when present, is 1.In an even further aspect, r, when present, is 2. In a still furtheraspect, r, when present, is 3.

In a further aspect, the purine derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the purine derivative has a structure representedby a formula:

or a pharmaceutically acceptable salt thereof.

a. R^(5A) and R^(5B) Groups

In one aspect, each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C8 alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and wherein eachof R^(5a) and R^(5b) is independently substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a further aspect, each of R^(5a) and R^(5b) isindependently selected from hydrogen, C1-C4 alkyl, (CH₂)_(q)R⁸, andC═O(CH₂)_(q)R⁸ and wherein each of R^(5a) and R^(5b) is independentlysubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl.

In a further aspect, each of R^(5a) and R^(5b) is independently selectedfrom hydrogen, C1-C8 alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and whereineach of R^(5a) and R^(5b) is independently substituted with 1 or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, each of R^(5a) and R^(5b)is independently selected from hydrogen, C1-C8 alkyl, (CH₂)_(q)R⁸, andC═O(CH₂)_(q)R⁸ and wherein each of R^(5a) and R^(5b) is independentlysubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, each of R^(5a)and R^(5b) is independently selected from hydrogen, C1-C8 alkyl,(CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and wherein each of R^(5a) and R^(5b) isindependently monosubstituted with a group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further aspect,each of R^(5a) and R^(5b) is independently selected from hydrogen, C1-C8alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and wherein each of R^(5a) andR^(5b) is unsubstituted.

In a further aspect, R^(5a), when present, is hydrogen and R^(5b) isselected from C1-C8 alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and whereinR^(5b) is substituted with 0, 1, or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In a still furtheraspect, R^(5a), when present, is hydrogen and R^(5b) is selected fromC1-C4 alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and wherein R^(5b) issubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl.

In a further aspect, R^(5a), when present, is hydrogen and R^(5b) isselected from C1-C8 alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and whereinR^(5b) is substituted with 1 or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In a still furtheraspect, R^(5a), when present, is hydrogen and R^(5b) is selected fromC1-C8 alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and wherein R^(5b) issubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(5a), whenpresent, is hydrogen and R^(5b) is selected from C1-C8 alkyl,(CH₂)_(q)R, and C═O(CH₂)_(q)R⁸ and wherein R^(5b) is monosubstitutedwith a group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In an even further aspect, R^(5a), when present, ishydrogen and R^(5b) is selected from C1-C8 alkyl, (CH₂)_(q)R⁸, andC═O(CH₂)_(q)R⁸ and wherein R^(5b) is unsubstituted.

In a further aspect, R^(5a), when present, is hydrogen and R^(5b) isselected from (CH₂)_(q)R⁸ and C═O(CH₂)_(q)R⁸ and wherein R^(5b) issubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,R^(5a), when present, is hydrogen and R^(5b) is selected from(CH₂)_(q)R⁸ and C═O(CH₂)_(q)R⁸ and wherein R^(5b) is substituted with 1or 2 groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(5a), whenpresent, is hydrogen and R^(5b) is selected from (CH₂)_(q)R⁸ andC═O(CH₂)_(q)R⁸ and wherein R^(5b) is substituted with 0 or 1 groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In aneven further aspect, R^(5a) when present, is hydrogen and R^(5b) isselected from (CH₂)_(q)R⁸ and C═O(CH₂)_(q)R⁸ and wherein R^(5b) ismonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R^(5a), whenpresent, is hydrogen and R^(5b) is selected from (CH₂)_(q)R⁸ andC═O(CH₂)_(q)R⁸ and wherein R^(5b) is unsubstituted.

In a further aspect, R^(5a), when present, is hydrogen and R^(5b) isC1-C8 alkyl substituted with 0, 1, or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, R^(5a), when present, is hydrogen and R^(5b) isC1-C4 alkyl substituted with 0, 1, or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In yeta further aspect, R^(5a), when present, is hydrogen and R^(5b) isselected from methyl, ethyl, n-propyl, and iso-propyl and wherein R^(5b)is substituted with 0, 1, or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In an even furtheraspect, R^(5a), when present, is hydrogen and R^(5b) is selected frommethyl and ethyl and wherein R^(5b) is substituted with 0, 1, or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(5a), when present, ishydrogen and R^(5b) is ethyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, R^(5a), when present, ishydrogen and R^(5b) is methyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl.

In a further aspect, R^(5a), when present, is hydrogen and R^(5b) isC1-C8 alkyl substituted with 1 or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In a still furtheraspect, R^(5a), when present, is hydrogen and R^(5b) is C1-C8 alkylsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(5a), whenpresent, is hydrogen and R^(5b) is C1-C8 alkyl monosubstituted with agroup selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In an even further aspect, R^(5a), when present, is hydrogen and R^(5b)is unsubstituted C1-C8 alkyl.

In a further aspect, R^(5a), when present, is hydrogen and R^(5b) isC1-C8 alkyl substituted with 1 or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl,C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl,C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl. In a still furtheraspect, R^(5a), when present, is hydrogen and R^(5b) is C1-C8 alkylsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl. In yet a further aspect, R^(5a), whenpresent, is hydrogen and R^(5b) is C1-C8 alkyl monosubstituted with agroup selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 monohaloalkyl,C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, R^(5a), when present, is hydrogen and R^(5b) isn-propyl monosubstituted with a C1-C4 hydroxyalkyl group. In a stillfurther aspect, R^(5a), when present, is hydrogen and R^(5b) is n-propylmonosubstituted with a C1-C2 hydroxyalkyl group. In yet a furtheraspect, R^(5a), when present, is hydrogen and R^(5b) is n-propylmonosubstituted with a —CH₂OH group.

b. R⁶ Groups

In one aspect, R⁶ is selected from halogen, OR⁹, and NR^(10a)R^(10b). Ina further aspect, R² is selected from OR⁹ and NR^(10a)R^(10b). In astill further aspect, R² is selected from halogen and OR⁹. In a yetfurther aspect, R² is selected from halogen and NR^(10a)R^(10b). In aneven further aspect, R² is halogen. In a still further aspect, R² isOR⁹. In a yet further aspect, R² is NR^(10a)R^(10b).

c. R⁷ Groups

In one aspect, R⁷, when present, is selected from hydrogen and C1-C8alkyl. In a further aspect, R⁷, when present, is selected from hydrogenand C1-C4 alkyl. In a still further aspect, R⁷, when present, ishydrogen.

In a further aspect, R⁷, when present, is selected from hydrogen,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andtert-butyl. In a still further aspect, R⁷, when present, is selectedfrom hydrogen, methyl, ethyl, n-propyl, and iso-propyl. In yet a furtheraspect, R⁷, when present, is selected from hydrogen, methyl, and ethyl.In an even further aspect, R⁷, when present, is selected from hydrogenand methyl. In a still further aspect, R⁷, when present, is selectedfrom hydrogen and ethyl.

In a further aspect, R⁷, when present, is selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. Ina still further aspect, R⁷, when present, is selected from methyl,ethyl, n-propyl, and iso-propyl. In yet a further aspect, R⁷, whenpresent, is selected from methyl, and ethyl. In an even further aspect,R⁷, when present, is methyl. In a still further aspect, R⁷, whenpresent, is ethyl. In yet a further aspect, R⁷, when present, isn-propyl. In an even further aspect, R⁷, when present, is iso-propyl.

d. R⁸ Groups

In one aspect, R⁸, when present, is selected from hydrogen, —OH, —SH,—NH₂, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and C1-C4dialkylamino. In a further aspect, R⁸, when present, is selected fromhydrogen, —OH, —SH, —NH₂, C1-C4 alkoxy, C1-C2 thioalkoxy, C1-C2alkylamino, and C1-C2 dialkylamino. In a still further aspect, R⁸, whenpresent, is hydrogen.

In a further aspect, R⁸, when present, is selected from hydrogen, C1-C4alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino. In astill further aspect, R⁸, when present, is selected from hydrogen, C1-C2alkoxy, C1-C2 thioalkoxy, C1-C2 alkylamino, and C1-C2 dialkylamino.

In a further aspect, R⁸, when present, is selected from hydrogen, —OH,—SH, and —NH₂. In a still further aspect, R⁸, when present, is selectedfrom hydrogen, —OH, and —SH. In yet a further aspect, R⁸, when present,is selected from hydrogen, —OH and —NH₂. In an even further aspect, R⁸,when present, is selected from hydrogen and —OH. In a still furtheraspect, R⁸, when present, is selected from hydrogen and —SH. In yet afurther aspect, R⁸, when present, is selected from hydrogen and —NH₂.

e. R⁹ Groups

In one aspect, R⁹, when present, is selected from C1-C8 alkyl,(CH₂)_(p)Cy¹, and (CH₂)_(p)Ar¹ and wherein R⁹, when present, issubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a further aspect, R⁹,when present, is selected from C1-C4 alkyl, (CH₂)_(p)Cy¹, and(CH₂)_(p)Ar¹ and wherein R⁹, when present, is substituted with 0, 1, or2 groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

In a further aspect, R⁹, when present, is selected from C1-C8 alkyl,(CH₂)_(p)Cy¹, and (CH₂)_(p)Ar¹ and wherein R⁹, when present, issubstituted with 1 or 2 groups independently selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,R⁹, when present, is selected from C1-C8 alkyl, (CH₂)_(p)Cy¹, and(CH₂)_(p)Ar¹ and wherein R⁹, when present, is substituted with 0 or 1group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In yet a further aspect, R⁹, when present, is selected from C1-C8 alkyl,(CH₂)_(p)Cy¹, and (CH₂)_(p)Ar¹ and wherein R⁹, when present, ismonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, R⁹, whenpresent, is selected from C1-C8 alkyl, (CH₂)_(p)Cy¹, and (CH₂)_(p)Ar¹and wherein R⁹, when present, is unsubstituted.

In a further aspect, R⁹, when present, is selected from (CH₂)_(p)Cy¹ and(CH₂)_(p)Ar¹ and wherein R⁹, when present, is substituted with 0, 1, or2 groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R⁹, whenpresent, is selected from (CH₂)_(p)Cy¹ and (CH₂)_(p)Ar¹ and wherein R⁹,when present, is substituted with 1 or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In yeta further aspect, R⁹, when present, is selected from (CH₂)_(p)Cy¹ and(CH₂)_(p)Ar¹ and wherein R⁹, when present, is substituted with 0 or 1group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In an even further aspect, R⁹, when present, is selected from(CH₂)_(p)Cy¹ and (CH₂)_(p)Ar¹ and wherein R⁹, when present, ismonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R⁹, whenpresent, is selected from (CH₂)_(p)Cy¹ and (CH₂)_(p)Ar¹ and wherein R⁹,when present, is unsubstituted.

In a further aspect, R⁹, when present, is (CH₂)_(p)Cy¹ and wherein R⁹,when present, is substituted with 0, 1, or 2 groups independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, R⁹, when present, is (CH₂)_(p)Cy¹ and wherein R⁹,when present, is substituted with 1 or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In yeta further aspect, R⁹, when present, is (CH₂)_(p)Cy¹ and wherein R⁹, whenpresent, is substituted with 0 or 1 group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further aspect,R⁹, when present, is (CH₂)_(p)Cy¹ and wherein R⁹, when present, issubstituted with a group selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R⁹, whenpresent, is (CH₂)_(p)Cy¹ and wherein R⁹, when present, is unsubstituted.

In a further aspect, R⁹, when present, is (CH₂)_(p)Ar¹ and wherein R⁹,when present, is substituted with 0, 1, or 2 groups independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, R⁹, when present, is (CH₂)_(p)Ar¹ and wherein R⁹,when present, is substituted with 1 or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In yeta further aspect, R⁹, when present, is (CH₂)_(p)Ar¹ and wherein R⁹, whenpresent, is substituted with 0 or 1 group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further aspect,R⁹, when present, is (CH₂)_(p)Ar¹ and wherein R⁹, when present, issubstituted with a group selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R⁹, whenpresent, is (CH₂)_(p)Ar¹ and wherein R⁹, when present, is unsubstituted.

In a further aspect, R⁹, when present, is C1-C8 alkyl and wherein R⁹,when present, is substituted with 0, 1, or 2 groups independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, R⁹, when present, is C1-C8 alkyl and wherein R⁹,when present, is substituted with 1 or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In yeta further aspect, R⁹, when present, is C1-C8 alkyl and wherein R⁹, whenpresent, is substituted with 0 or 1 group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further aspect,R⁹, when present, is C1-C8 alkyl and wherein R⁹, when present, issubstituted with a group selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R⁹, whenpresent, is C1-C8 alkyl and wherein R⁹, when present, is unsubstituted.

In a further aspect, R⁹, when present, is C1-C8 alkyl. In a stillfurther aspect, R⁹, when present, is selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. Inyet a further aspect, R⁹, when present, is selected from methyl, ethyl,n-propyl, and iso-propyl. In an even further aspect, R⁹, when present,is selected from methyl and ethyl. In a still further aspect, R⁹, whenpresent, is ethyl. In yet a further aspect, R⁹, when present, is methyl.

f. R^(10A) and R^(10B) Groups

In one aspect, each of R^(10a) and R^(10b), when present, isindependently selected from C1-C8 alkyl, Cy², Ar², (CH₂)_(r)Cy², and(CH₂)_(r)Ar² and wherein each of R^(10a) and R^(10b) is independentlysubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a further aspect, eachof R^(10a) and R^(10b), when present, is independently selected fromC1-C4 alkyl, Cy², Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² and wherein eachof R^(10a) and R^(10b) is independently substituted with 0, 1, or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl.

In a further aspect, each of R^(10a) and R^(10b), when present, isindependently selected from C1-C8 alkyl, Cy², Ar², (CH₂)_(r)Cy², and(CH₂)_(r)Ar² and wherein each of R^(10a) and R^(10b) is independentlysubstituted with 1 or 2 groups independently selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,each of R^(10a) and R^(10b), when present, is independently selectedfrom C1-C8 alkyl, Cy², Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² and whereineach of R^(10a) and R^(10b) is independently substituted with 0 or 1group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In yet a further aspect, each of R^(10a) and R^(10b), when present, isindependently selected from C1-C8 alkyl, Cy², Ar², (CH₂)_(r)Cy², and(CH₂)_(r)Ar² and wherein each of R^(10a) and R^(10b) is independentlymonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, each of R^(10a)and R^(10b), when present, is independently selected from C1-C8 alkyl,Cy², Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² and wherein each of R^(10a) andR^(10b) is unsubstituted.

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is selected from C1-C8 alkyl, Cy², Ar², (CH₂)_(r)Cy², and(CH₂)_(r)Ar² and wherein R^(10b) is substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is selected from C1-C4 alkyl, Cy²,Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² and wherein R^(10b) is substitutedwith 0, 1, or 2 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl.

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is selected from C1-C8 alkyl, Cy², Ar², (CH₂)_(r)Cy², and(CH₂)_(r)Ar² and wherein R^(10b) is substituted with 1 or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is selected from C1-C8 alkyl, Cy²,Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² and wherein R^(10b) is substitutedwith 0 or 1 group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is selected from C1-C8 alkyl, Cy²,Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² and wherein R^(10b) ismonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, R^(10a) whenpresent, is hydrogen and R^(10b), when present, is selected from C1-C8alkyl, Cy², Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² and wherein R^(10b) isunsubstituted.

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is C1-C8 alkyl and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is C1-C4 alkyl and substituted with0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is selected from methyl,ethyl, n-propyl, and iso-propyl and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In an even further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is selected from methyl and ethyland substituted with 0, 1, or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In a still furtheraspect, R^(10a), when present, is hydrogen and R^(10b), when present, isethyl substituted with 0, 1, or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a furtheraspect, R^(10a), when present, is hydrogen and R^(10b), when present, ismethyl substituted with 0, 1, or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is C1-C8 alkyl and substituted with 1 or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is C1-C8 alkyl and substituted with0 or 1 group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is C1-C8 alkyl and monosubstitutedwith a group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In an even further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is unsubstituted C1-C8 alkyl.

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is selected from Cy² and (CH₂)_(r)Cy² and wherein R^(10b)is substituted with 0, 1, or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In a still furtheraspect, R^(10a), when present, is hydrogen and R^(10b), when present, isselected from Cy² and (CH₂)_(r)Cy² and wherein R^(10b) is substitutedwith 1 or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is selected from Cy² and(CH₂)_(r)Cy² and wherein R^(10b) is substituted with 0 or 1 groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In aneven further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is selected from Cy² and (CH₂)_(r)Cy² and wherein R^(10b)is monosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is selected from Cy² and(CH₂)_(r)Cy² and wherein R^(10b) is unsubstituted.

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is Cy² and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is Cy² and substituted with 1 or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is Cy² and substituted with 0 or 1group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In an even further aspect, R^(10a), when present, is hydrogen andR^(10b), when present, is Cy² and monosubstituted with a group selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is unsubstituted Cy².

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is (CH₂)_(r)Cy² and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is (CH₂)_(r)Cy² and substituted with1 or 2 groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is (CH₂)_(r)Cy² andsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is (CH₂)_(r)Cy² andmonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is unsubstituted(CH₂)_(r)Cy².

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is CH₂Cy² and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is CH₂Cy² and substituted with 1 or2 groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is CH₂Cy² andsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is CH₂Cy² andmonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is unsubstituted CH₂Cy².

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is selected from Ar² and (CH₂)_(r)Ar² and wherein R^(10b)is substituted with 0, 1, or 2 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In a still furtheraspect, R^(10a), when present, is hydrogen and R^(10b), when present, isselected from Ar² and (CH₂)_(r)Ar² and wherein R^(10b) is substitutedwith 1 or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is selected from Ar² and(CH₂)_(r)Ar² and wherein R^(10b) is substituted with 0 or 1 groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In aneven further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is selected from Ar² and (CH₂)_(r)Ar² and wherein R^(10b)is monosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is selected from Ar² and(CH₂)_(r)Ar² and wherein R^(10b) is unsubstituted.

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is Ar² and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is Ar² and substituted with 1 or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is Ar² and substituted with 0 or 1group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In an even further aspect, R^(10a), when present, is hydrogen andR^(10b), when present, is Ar² and monosubstituted with a group selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is unsubstituted Ar².

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is (CH₂)_(r)Ar² and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is (CH₂)_(r)Ar² and substituted with1 or 2 groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is (CH₂)_(r)Ar² andsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is (CH₂)_(r)Ar² andmonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is unsubstituted(CH₂)_(r)Ar².

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is (CH₂)Ar² and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is (CH₂)Ar² and substituted with 1or 2 groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In yet a further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is (CH₂)Ar² andsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is (CH₂)Ar² andmonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, R^(10a), whenpresent, is hydrogen and R^(10b), when present, is unsubstituted(CH₂)Ar².

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is (CH₂)Ar² and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, and —NH₂. In astill further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is (CH₂)Ar² and substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, and —NH₂. In yet a furtheraspect, R^(10a), when present, is hydrogen and R^(10b), when present, is(CH₂)Ar² and substituted with 0, 1, or 2 groups independently selectedfrom —OH and —NH₂. In an even further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is (CH₂)Ar² and substituted with 0,1, or 2 —OH groups. In a still further aspect, R^(10a), when present, ishydrogen and R^(10b), when present, is (CH₂)Ar² and substituted with 0,1, or 2 —NH₂ groups.

In a further aspect, R^(10a), when present, is hydrogen and R^(10b),when present, is (CH₂)Ar² monosubstituted with an —OH group.

g. CY¹ Groups

In one aspect, Cy¹, when present, is selected from C3-C6 cycloalkyl andC3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a further aspect, Cy¹, when present, isselected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, Cy¹, when present, is selected from C3-C6cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, Cy¹, whenpresent, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyland substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further aspect,Cy¹, when present, is selected from C3-C6 cycloalkyl and C3-C6heterocycloalkyl and monosubstituted with a group selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In aneven further aspect, Cy¹, when present, is selected from C3-C6cycloalkyl and C3-C6 heterocycloalkyl and unsubstituted.

In a further aspect, Cy¹, when present, is C3-C6 cycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, Cy¹, when present, is C3-C6 cycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, Cy¹, when present, is C3-C6 cycloalkyl andsubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, Cy¹, when present, is C3-C6 cycloalkyl andsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further aspect,Cy¹, when present, is C3-C6 cycloalkyl and monosubstituted with a groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In an even further aspect, Cy¹, when present, isunsubstituted C3-C6 cycloalkyl.

In a further aspect, Cy¹, when present, is C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, Cy¹, when present, is C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, Cy¹, when present, is C3-C6 heterocycloalkyl andsubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, Cy¹, when present, is C3-C6 heterocycloalkyl andsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further aspect,Cy¹, when present, is C3-C6 heterocycloalkyl and monosubstituted with agroup selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In an even further aspect, Cy¹, when present, isunsubstituted C3-C6 heterocycloalkyl.

h. CY² Groups

In one aspect, Cy², when present, is selected from C3-C6 cycloalkyl andC3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a further aspect, Cy², when present, isselected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, Cy², when present, is selected from C3-C6cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In a still further aspect, Cy², whenpresent, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyland substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further aspect,Cy², when present, is selected from C3-C6 cycloalkyl and C3-C6heterocycloalkyl and monosubstituted with a group selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In aneven further aspect, Cy², when present, is selected from C3-C6cycloalkyl and C3-C6 heterocycloalkyl and unsubstituted.

In a further aspect, Cy², when present, is C3-C6 cycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, Cy², when present, is C3-C6 cycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, Cy², when present, is C3-C6 cycloalkyl andsubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, Cy², when present, is C3-C6 cycloalkyl andsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further aspect,Cy², when present, is C3-C6 cycloalkyl and monosubstituted with a groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In an even further aspect, Cy², when present, isunsubstituted C3-C6 cycloalkyl.

In a further aspect, Cy², when present, is C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, Cy², when present, is C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, Cy², when present, is C3-C6 heterocycloalkyl andsubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In astill further aspect, Cy², when present, is C3-C6 heterocycloalkyl andsubstituted with 0 or 1 group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a further aspect,Cy², when present, is C3-C6 heterocycloalkyl and monosubstituted with agroup selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In an even further aspect, Cy², when present, isunsubstituted C3-C6 heterocycloalkyl.

i. AR¹ Groups

In one aspect, Ar¹, when present, is selected from aryl and heteroaryland substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In afurther aspect, Ar¹, when present, is selected from aryl and heteroaryland substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, Ar¹, when present, is selected from aryl andheteroaryl and substituted with 0, 1, or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In a still further aspect, Ar¹, when present, is selected from aryl andheteroaryl and substituted with 0 or 1 group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a furtheraspect, Ar¹, when present, is selected from aryl and heteroaryl andmonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further aspect,Ar¹, when present, is selected from aryl and heteroaryl andunsubstituted.

In a further aspect, Ar¹, when present, is aryl and substituted with 0,1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar¹, when present, is aryl and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl.

In a further aspect, Ar¹, when present, is aryl and substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar¹, when present, is aryl and substituted with 0 or 1 group selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In yet a further aspect, Ar¹, when present, is aryl and monosubstitutedwith a group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, Ar¹, whenpresent, is unsubstituted aryl.

In a further aspect, Ar¹, when present, is phenyl and substituted with0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar¹, when present, is phenyl and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl.

In a further aspect, Ar¹, when present, is phenyl and substituted with0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar¹, when present, is phenyl and substituted with 0 or 1 group selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In yet a further aspect, Ar¹, when present, is phenyl andmonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further aspect,Ar¹, when present, is unsubstituted phenyl.

In a further aspect, Ar¹, when present, is heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar¹, when present, is heteroaryl and substituted with 0, 1, 2, or 3groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl.

In a further aspect, Ar¹, when present, is heteroaryl and substitutedwith 0, 1, or 2 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar¹, when present, is heteroaryl and substituted with 0 or 1 groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, Ar¹, when present, isheteroaryl and monosubstituted with a group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In an even furtheraspect, Ar¹, when present, is unsubstituted heteroaryl.

In a further aspect, Ar¹, when present, is pyridinyl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar¹, when present, is pyridinyl and substituted with 0, 1, 2, or 3groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl.

In a further aspect, Ar¹, when present, is pyridinyl and substitutedwith 0, 1, or 2 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar¹, when present, is pyridinyl and substituted with 0 or 1 groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, Ar¹, when present, ispyridinyl and monosubstituted with a group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In an even furtheraspect, Ar¹, when present, is unsubstituted pyridinyl.

j. AR² Groups

In one aspect, Ar², when present, is selected from aryl and heteroaryland substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In afurther aspect, Ar², when present, is selected from aryl and heteroaryland substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.

In a further aspect, Ar², when present, is selected from aryl andheteroaryl and substituted with 0, 1, or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In a still further aspect, Ar², when present, is selected from aryl andheteroaryl and substituted with 0 or 1 group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In yet a furtheraspect, Ar², when present, is selected from aryl and heteroaryl andmonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further aspect,Ar², when present, is selected from aryl and heteroaryl andunsubstituted.

In a further aspect, Ar², when present, is aryl and substituted with 0,1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar², when present, is aryl and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl.

In a further aspect, Ar², when present, is aryl and substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar², when present, is aryl and substituted with 0 or 1 group selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In yet a further aspect, Ar², when present, is aryl and monosubstitutedwith a group selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl. In an even further aspect, Ar², whenpresent, is unsubstituted aryl.

In a further aspect, Ar², when present, is phenyl and substituted with0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar², when present, is phenyl and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl.

In a further aspect, Ar², when present, is phenyl and substituted with0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar², when present, is phenyl and substituted with 0 or 1 group selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.In yet a further aspect, Ar², when present, is phenyl andmonosubstituted with a group selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In an even further aspect,Ar², when present, is unsubstituted phenyl.

In a further aspect, Ar², when present, is heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar², when present, is heteroaryl and substituted with 0, 1, 2, or 3groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl.

In a further aspect, Ar², when present, is heteroaryl and substitutedwith 0, 1, or 2 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar², when present, is heteroaryl and substituted with 0 or 1 groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, Ar², when present, isheteroaryl and monosubstituted with a group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In an even furtheraspect, Ar², when present, is unsubstituted heteroaryl.

In a further aspect, Ar², when present, is pyridinyl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar², when present, is pyridinyl and substituted with 0, 1, 2, or 3groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylaminomethyl.

In a further aspect, Ar², when present, is pyridinyl and substitutedwith 0, 1, or 2 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl. In a still further aspect,Ar², when present, is pyridinyl and substituted with 0 or 1 groupselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl. In yet a further aspect, Ar², when present, ispyridinyl and monosubstituted with a group selected from halogen, —OH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl. In an even furtheraspect, Ar², when present, is unsubstituted pyridinyl.

3. 3-(2-Phenylhydrazono)indolin-2-one Derivatives

In one aspect, disclosed are 3-(2-phenylhydrazono)indolin-2-onederivatives having a structure represented by a formula:

wherein each of R^(11a), R^(11b), R^(11c), and R^(11d) is independentlyselected from hydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵; wherein each occurrence of R¹⁵, whenpresent, is independently selected from hydrogen, —CH₃, —CFH₂, —CF₂H,—CF₃, —NH₂, —NH(CH₃), and —N(CH₃)₂; wherein each of R¹² and R¹³ isindependently selected from hydrogen and C1-C4 alkyl; wherein each ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4dialkylamino, —SO₂R¹⁶ and —CO₂R¹⁶; and wherein each occurrence of R¹⁶,when present, is independently selected from hydrogen, —CH₃, —CFH₂,—CF₂H, —CF₃, —NH₂, —NH(CH₃), and —N(CH₃)₂, or a pharmaceuticallyacceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the 3-(2-phenylhydrazono)indolin-2-one derivativehas a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

a. R^(11A), R^(11B), R^(11C), AND R^(11D) Groups

In one aspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen, halogen, —OH, —SH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a furtheraspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) is independentlyselected from hydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl,C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In yet a further aspect, each ofR^(11a), R^(11b), R^(11c), and R^(11d) is hydrogen.

In a further aspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect, eachof R^(11a), R^(11b), R^(11c), and R^(11d) is independently selected fromhydrogen, halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2dialkylamino. In yet a further aspect, each of R^(11a), R^(11b),R^(11c), and R^(11d) is independently selected from hydrogen, —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylamino. In a still further aspect, each of R^(11a), R^(11b),R^(11c), and R^(11d) is independently selected from hydrogen, halogen,C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, each ofR^(11a), R^(11b), R^(11c), and R^(11d) is independently selected fromhydrogen, —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and—N(CH₃)₂.

In a further aspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4polyhaloalkyl. In a still further aspect, each of R^(11a), R^(11b),R^(11c), and R^(11d) is independently selected from hydrogen, C1-C2monohaloalkyl, and C1-C2 polyhaloalkyl. In yet a further aspect, each ofR^(11a), R^(11b), R^(11c), and R^(11d) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen and C1-C4 alkyl. In a still furtheraspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) is independentlyselected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yeta further aspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen, methyl, and ethyl. In an evenfurther aspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen and methyl. In a still furtheraspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) is independentlyselected from hydrogen and ethyl.

In a further aspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen and halogen. In a still furtheraspect, each of R^(11a), R^(11b), R^(11c), and R^(11d) is independentlyselected from hydrogen, —F, —Cl, and —Br. In yet a further aspect, eachof R^(11a), R^(11b), R^(11c), and R^(11d) is independently selected fromhydrogen, —F, and —Cl. In an even further aspect, each of R^(11a),R^(11b), R^(11c), and R^(11d) is independently selected from hydrogenand —F. In a still further aspect, each of R^(11a), R^(11b), R^(11c),and R^(11d) is independently selected from hydrogen and —Cl.

In a further aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c),and R^(11d) is independently selected from hydrogen, halogen, —OH, —SH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a stillfurther aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c), andR^(11d) is independently selected from hydrogen, halogen, —OH, —SH, —CN,—NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵.

In a further aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c),and R^(11d) is independently selected from hydrogen, halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(11a) is hydrogen and each of R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂,C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, R^(11a)is hydrogen and each of R^(11b), R^(11c), and R^(11d) is independentlyselected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂,—CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c),and R^(11d) is independently selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylamino. In a still further aspect, R^(11a) is hydrogenand each of R^(11b), R^(11c), and R^(11d) is independently selected fromhydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c), andR^(11d) is independently selected from hydrogen, —F, —Cl, —Br, —CH₃,—CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c),and R^(11d) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(11a) is hydrogen and each of R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(11a) is hydrogen and each ofR^(11b), R^(11c), and R^(11d) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c),and R^(11d) is independently selected from hydrogen and C1-C4 alkyl. Ina still further aspect, R^(11a) is hydrogen and each of R^(11b),R^(11c), and R^(11d) is independently selected from hydrogen, methyl,ethyl, iso-propyl, and n-propyl. In yet a further aspect, R^(11a) ishydrogen and each of R^(11b), R^(11c), and R^(11d) is independentlyselected from hydrogen, methyl, and ethyl. In an even further aspect,R^(11a) is hydrogen and each of R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen and methyl. In a still furtheraspect, R^(11a) is hydrogen and each of R^(11b), R^(11c), and R^(11d) isindependently selected from hydrogen and ethyl.

In a further aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c),and R^(11d) is independently selected from hydrogen and halogen. In astill further aspect, R^(11a) is hydrogen and each of R^(11b), R^(11c),and R^(11d) is independently selected from hydrogen, —F, —Cl, and —Br.In yet a further aspect, R^(11a) is hydrogen and each of R^(11b),R^(11c), and R^(11d) is independently selected from hydrogen, —F, and—Cl. In an even further aspect, R^(11a) is hydrogen and each of R^(11b),R^(11c), and R^(11d) is independently selected from hydrogen and —F. Ina still further aspect, R^(11a) is hydrogen and each of R^(11b),R^(11c), and R^(11d) is independently selected from hydrogen and —Cl.

In a further aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c),and R^(11d) is independently selected from hydrogen, halogen, —OH, —SH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a stillfurther aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c), andR^(11d) is independently selected from hydrogen, halogen, —OH, —SH, —CN,—NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵.

In a further aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c),and R^(11d) is independently selected from hydrogen, halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(11b) is hydrogen and each of R^(11a), R^(11c), and R^(11d) isindependently selected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂,C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, R^(11b)is hydrogen and each of R^(11a), R^(11c), and R^(11d) is independentlyselected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂,—CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c),and R^(11d) is independently selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylamino. In a still further aspect, R^(11b) is hydrogenand each of R^(11a), R^(11C), and R^(11d) is independently selected fromhydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c), andR^(11d) is independently selected from hydrogen, —F, —Cl, —Br, —CH₃,—CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c),and R^(11d) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(11b) is hydrogen and each of R^(11a), R^(11c), and R^(11d) isindependently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(11b) is hydrogen and each ofR^(11a), R^(11c), and R^(11d) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c),and R^(11d) is independently selected from hydrogen and C1-C4 alkyl. Ina still further aspect, R^(11b) is hydrogen and each of R^(11a),R^(11c), and R^(11d) is independently selected from hydrogen, methyl,ethyl, iso-propyl, and n-propyl. In yet a further aspect, R^(11b) ishydrogen and each of R^(11a), R^(11c), and R^(11d) is independentlyselected from hydrogen, methyl, and ethyl. In an even further aspect,R^(11b) is hydrogen and each of R^(11a), R^(11c), and R^(11d) isindependently selected from hydrogen and methyl. In a still furtheraspect, R^(11b) is hydrogen and each of R^(11a), R^(11c), and R^(11d) isindependently selected from hydrogen and ethyl.

In a further aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c),and R^(11d) is independently selected from hydrogen and halogen. In astill further aspect, R^(11b) is hydrogen and each of R^(11a), R^(11c),and R^(11d) is independently selected from hydrogen, —F, —Cl, and —Br.In yet a further aspect, R^(11b) is hydrogen and each of R^(11a),R^(11c), and R^(11d) is independently selected from hydrogen, —F, and—Cl. In an even further aspect, R^(11b) is hydrogen and each of R^(11a),R^(11c), and R^(11d) is independently selected from hydrogen and —F. Ina still further aspect, R^(11b) is hydrogen and each of R^(11a),R^(11c), and R^(11d) is independently selected from hydrogen and —Cl.

In a further aspect, R^(11C) is hydrogen and each of R^(11a), R^(11b),and R^(11c) is independently selected from hydrogen, halogen, —OH, —SH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a stillfurther aspect, R^(11c) is hydrogen and each of R^(11a), R^(11b), andR^(11d) is independently selected from hydrogen, halogen, —OH, —SH, —CN,—NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁵, and —CO₂R₅.

In a further aspect, R^(11c) is hydrogen and each of R^(11a), R^(11b),and R^(11d) is independently selected from hydrogen, halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(11c) is hydrogen and each of R^(11a), R^(11b), and R^(11d) isindependently selected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂,C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, R^(11c)is hydrogen and each of R^(11a), R^(11b), and R^(11c) is independentlyselected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂,—CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R^(11c) is hydrogen and each of R^(11a), R^(11b),and R^(11d) is independently selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylamino. In a still further aspect, R^(11c) is hydrogenand each of R^(11a), R^(11b), and R^(11d) is independently selected fromhydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(11c) is hydrogen and each of R^(11a), R^(11b), andR^(11i) is independently selected from hydrogen, —F, —Cl, —Br, —CH₃,—CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R^(11c) is hydrogen and each of R^(11a), R^(11b),and R^(11d) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(11c) is hydrogen and each of R^(11a), R^(11b), and R^(11d) isindependently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(11c) is hydrogen and each ofR^(11a), R^(11b), and R^(11d) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(11c) is hydrogen and each of R^(11a), R^(11b),and R^(11d) is independently selected from hydrogen and C1-C4 alkyl. Ina still further aspect, R^(11c) is hydrogen and each of R^(11a),R^(11b), and R^(11d) is independently selected from hydrogen, methyl,ethyl, iso-propyl, and n-propyl. In yet a further aspect, R^(11c) ishydrogen and each of R^(11a), R^(11b), and R^(11d) is independentlyselected from hydrogen, methyl, and ethyl. In an even further aspect,R^(11c) is hydrogen and each of R^(11a), R^(11b), and R^(11d) isindependently selected from hydrogen and methyl. In a still furtheraspect, R^(11c) is hydrogen and each of R^(11a), R^(11b), and R^(11d) isindependently selected from hydrogen and ethyl.

In a further aspect, R^(11c) is hydrogen and each of R^(11a), R^(11b),and R^(11d) is independently selected from hydrogen and halogen. In astill further aspect, R^(11c) is hydrogen and each of R^(11a), R^(11b),and R^(11d) is independently selected from hydrogen, —F, —Cl, and —Br.In yet a further aspect, R^(11c) is hydrogen and each of R^(11a),R^(11b), and R^(11d) is independently selected from hydrogen, —F, and—Cl. In an even further aspect, R^(11c) is hydrogen and each of R^(11a),R^(11b), and R^(11d) is independently selected from hydrogen and —F. Ina still further aspect, R^(11c) is hydrogen and each of R^(11a),R^(11b), and R^(11d) is independently selected from hydrogen and —Cl.

In a further aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b),and R^(11c) is independently selected from hydrogen, halogen, —OH, —SH,—CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a stillfurther aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b), andR^(11c) is independently selected from hydrogen, halogen, —OH, —SH, —CN,—NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵.

In a further aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b),and R^(11c) is independently selected from hydrogen, halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(11d) is hydrogen and each of R^(11a), R^(11b), and R^(11c) isindependently selected from hydrogen, halogen, —OH, —CN, —NO₂, —NH₂,C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, R^(11d)is hydrogen and each of R^(11a), R^(11b), and R^(11c) is independentlyselected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂,—CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b),and R^(11c) is independently selected from hydrogen, halogen, C1-C4alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylamino. In a still further aspect, R^(11d) is hydrogenand each of R^(11a), R^(11b), and R^(11c) is independently selected fromhydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b), andR^(11c) is independently selected from hydrogen, —F, —Cl, —Br, —CH₃,—CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b),and R^(11c) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(11d) is hydrogen and each of R^(11a), R^(11b), and R^(11c) isindependently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(11d) is hydrogen and each ofR^(11a), R^(11b), and R^(11c) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b),and R^(11c) is independently selected from hydrogen and C1-C4 alkyl. Ina still further aspect, R^(11d) is hydrogen and each of R^(11a),R^(11b), and R^(11c) is independently selected from hydrogen, methyl,ethyl, iso-propyl, and n-propyl. In yet a further aspect, R^(11d) ishydrogen and each of R^(11a), R^(11b), and R^(11c) is independentlyselected from hydrogen, methyl, and ethyl. In an even further aspect,R^(11d) is hydrogen and each of R^(11a), R^(11b), and R^(11c) isindependently selected from hydrogen and methyl. In a still furtheraspect, R^(11d) is hydrogen and each of R^(11a), R^(11b), and R^(11c) isindependently selected from hydrogen and ethyl.

In a further aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b),and R^(11c) is independently selected from hydrogen and halogen. In astill further aspect, R^(11d) is hydrogen and each of R^(11a), R^(11b),and R^(11c) is independently selected from hydrogen, —F, —Cl, and —Br.In yet a further aspect, R^(11d) is hydrogen and each of R^(11a),R^(11b), and R^(11c) is independently selected from hydrogen, —F, and—Cl. In an even further aspect, R^(11d) is hydrogen and each of R^(11a),R^(11b), and R^(11c) is independently selected from hydrogen and —F. Ina still further aspect, R^(11d) is hydrogen and each of R^(11a),R^(11b), and R^(11c) is independently selected from hydrogen and —Cl.

In a further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a still further aspect, twoof R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and two ofR^(11a), R^(11b), R^(11c), and R^(11d) are independently selected fromhalogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁵,and —CO₂R¹⁵.

In a further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylamino. In a still further aspect, two of R^(11a),R^(11b), R^(11c), and R^(11d) are hydrogen and two of R^(11a), R^(11b),R^(11c), and R^(11d) are independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, two ofR^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and two of R^(11a),R^(11b), R^(11c), and R^(11d) is independently selected from —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In astill further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl,C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yeta further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) isindependently selected from —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃,—OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl.In a still further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d)are hydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl.In yet a further aspect, two of R^(11a), R^(11b), Riec, and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from —CFH₂, —CF₂H, and —CF₃.

In a further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from C1-C4 alkyl. In a still further aspect, twoof R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and two ofR^(11a), R^(11b), R^(11c), and R^(11d) are independently selected frommethyl, ethyl, iso-propyl, and n-propyl. In yet a further aspect, two ofR^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and two of R^(11a),R^(11b), R^(11c), and R^(11d) are independently selected from methyl andethyl. In an even further aspect, two of R^(11a), R^(11b), R^(11c), andR^(11d) are hydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d)are methyl. In a still further aspect, two of R^(11a), R^(11b), R^(11c),and R^(11d) are hydrogen and two of R^(11a), R^(11b), R^(11c), andR^(11d) are ethyl.

In a further aspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d) areindependently selected from halogen. In a still further aspect, two ofR^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and two of R^(11a),R^(11b), R^(11c), and R^(11d) are independently selected from —F, —Cl,and —Br. In yet a further aspect, two of R^(11a), R^(11b), R^(11c), andR^(11d) are hydrogen and two of R^(11a), R^(11b), R^(11c), and R^(11d)are independently selected from —F and —Cl. In an even further aspect,two of R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and two ofR^(11a), R^(11b), R^(11c), and R^(11d) are —F. In a still furtheraspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen andtwo of R^(11a), R^(11b), R^(11c), and R^(11d) are —Cl. In yet a furtheraspect, two of R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen andtwo of R^(11a), R^(11b), R^(11c), and R^(11d) are —Br.

In a further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is selectedfrom halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a still further aspect, three ofR^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and one of R^(11a),R^(11b), R^(11c), and R^(11d) is selected from halogen, —OH, —SH, —CN,—NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵.

In a further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In astill further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d)are hydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) isselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2dialkylamino. In yet a further aspect, three of R^(11a), R^(11b),R^(11c), and R^(11d) are hydrogen and one of R^(11a), R^(11b), R^(11c),and R^(11d) is selected from —F, —Cl, —Br, —OH, —CN, —NO₂, —NH₂, —CH₃,—CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is selectedfrom halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,three of R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and one ofR^(11a), R^(11b), R^(11c), and R^(11d) is selected from halogen, C1-C2alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylamino. In yet a further aspect, three of R^(11a),R^(11b), R^(11c), and R^(11d) are hydrogen and one of R^(11a), R^(11b),R^(11c), and R^(11d) is selected from —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H,—CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is selectedfrom C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl. In a still furtheraspect, three of R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen andone of R^(11a), R^(11b), R^(11c) and R^(11d) is selected from C1-C2monohaloalkyl and C1-C2 polyhaloalkyl. In yet a further aspect, three ofR^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and one of R^(11a),R^(11b), R^(11c), and R^(11d) is selected from —CFH₂, —CF₂H, and —CF₃.

In a further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is selectedfrom C1-C4 alkyl. In a still further aspect, three of R^(11a), R^(11b),R^(11c), and R^(11d) are hydrogen and one of R^(11a), R^(11b), R^(11c),and R^(11d) is selected from methyl, ethyl, iso-propyl, and n-propyl. Inyet a further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d)are hydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) isselected from methyl and ethyl. In an even further aspect, three ofR^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and one of R^(11a),R^(11b), R^(11c), and R^(11d) is methyl. In a still further aspect,three of R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and one ofR^(11a), R^(11b), R^(11c), and R^(11d) is ethyl.

In a further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d) arehydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is selectedfrom halogen. In a still further aspect, three of R^(11a), R^(11b),R^(11c) and R^(11d) are hydrogen and one of R^(11a), R^(11b), R^(11c),and R^(11d) is selected from —F, —Cl, and —Br. In yet a further aspect,three of R^(11a), R^(11b), R^(11c), and R^(11d) are hydrogen and one ofR^(11a), R^(11b), R^(11c), and R^(11d) is selected from —F and —Cl. Inan even further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d)are hydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is —F. Ina still further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d)are hydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is —Cl.In yet a further aspect, three of R^(11a), R^(11b), R^(11c), and R^(11d)are hydrogen and one of R^(11a), R^(11b), R^(11c), and R^(11d) is —Br.

b. R¹² and R¹³ Groups

In one aspect, each of R¹² and R¹³ is independently selected fromhydrogen and C1-C4 alkyl. In a further aspect, each of R¹² and R¹³ ishydrogen.

In a further aspect, each of R¹² and R¹³ is independently selected fromhydrogen, methyl, ethyl, n-propyl, and iso-propyl. In a still furtheraspect, each of R¹² and R¹³ is independently selected from hydrogen,methyl, and ethyl. In yet a further aspect, each of R¹² and R¹³ isindependently selected from hydrogen and ethyl. In an even furtheraspect, each of R¹² and R¹³ is independently selected from hydrogen andmethyl.

In a further aspect, R¹² is hydrogen and R¹³ is C1-C4 alkyl. In a stillfurther aspect, R¹² is hydrogen and R¹³ is selected from methyl, ethyl,n-propyl, and iso-propyl. In yet a further aspect, R¹² is hydrogen andR¹³ is selected from methyl and ethyl. In an even further aspect, R¹² ishydrogen and R¹³ is ethyl. In a still further aspect, R¹² is hydrogenand R¹³ is methyl.

In a further aspect, R¹³ is hydrogen and R¹² is C1-C4 alkyl. In a stillfurther aspect, R¹³ is hydrogen and R¹² is selected from methyl, ethyl,n-propyl, and iso-propyl. In yet a further aspect, R¹³ is hydrogen andR¹² is selected from methyl and ethyl. In an even further aspect, R¹³ ishydrogen and R¹² is ethyl. In a still further aspect, R¹³ is hydrogenand R¹² is methyl.

c. R^(14A), R^(14B), R^(14C), R^(14D), AND R^(14E) Groups

In one aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁶, and —CO₂R¹⁶. In a stillfurther aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO₂,—NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁶, and —CO₂R¹⁶.

In a further aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen, halogen, —OH, —SH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect, eachof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl,C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2dialkylamino.

In a further aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen, halogen, C1-C4 alkyl,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylamino. In a still further aspect, each of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, —F, —Cl, —Br, —CH₃, —CFH₂,—CF₂H, —CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen, C1-C4 monohaloalkyl,and C1-C4 polyhaloalkyl. In a still further aspect, each of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl. In yet a furtheraspect, each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) isindependently is selected from hydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen and C1-C4 alkyl. In astill further aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen, methyl, ethyl,iso-propyl, and n-propyl. In yet a further aspect, each of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, methyl, and ethyl. In an even further aspect, each of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen and methyl. In a still further aspect, each of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen and ethyl.

In a further aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen and halogen. In a stillfurther aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, —F, —Cl, and —Br. In yet afurther aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, —F, and —Cl. In an even furtheraspect, each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) isindependently selected from hydrogen and —F. In a still further aspect,each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen and —Cl.

In a further aspect, each of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen, —OH, —SH, —CN, —NO₂,—NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In a still further aspect, each of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, —OH, —SH, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In yet a further aspect,each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen, —SO₂R¹⁶, and —CO₂R¹⁶. In an even further aspect,each of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen and —SO₂R¹⁶. In a still further aspect, each ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen and —CO₂R¹⁶.

In a further aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁶and —CO₂R¹⁶. In a still further aspect, R^(14a) is hydrogen and each ofR^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2dialkylamino, —SO₂R¹⁶ and —CO₂R¹⁶.

In a further aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a stillfurther aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(14a) is hydrogen and each of R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2dialkylamino. In yet a further aspect, R^(14a) is hydrogen and each ofR^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and—N(CH₃)₂.

In a further aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(14a) is hydrogen and each of R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(14a) is hydrogen and each ofR^(14b), R^(14c), R^(14d), and R^(14e) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen and C1-C4alkyl. In a still further aspect, R^(14a) is hydrogen and each ofR^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a furtheraspect, R^(14a) is hydrogen and each of R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen, methyl, and ethyl. Inan even further aspect, R^(14a) is hydrogen and each of R^(14b),R^(14c), R^(14d), and R^(14e) is independently selected from hydrogenand methyl. In a still further aspect, R^(14a) is hydrogen and each ofR^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen and ethyl.

In a further aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen andhalogen. In a still further aspect, R^(14a) is hydrogen and each ofR^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, —F, —Cl, and —Br. In yet a further aspect, R^(14a) is hydrogenand each of R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen, —F, and —Cl. In an even further aspect, R^(14a)is hydrogen and each of R^(14b), R^(14c), R^(14d), and R^(14e) isindependently selected from hydrogen and —F. In a still further aspect,R^(14a) is hydrogen and each of R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen and —Cl.

In a further aspect, R^(14a) is hydrogen and each of R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, —OH, —SH,—CN, —NO₂, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In a still further aspect,R^(14a) is hydrogen and each of R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, —OH, —SH, —NH₂, —SO₂R¹⁶, and—CO₂R¹⁶. In yet a further aspect, R^(14a) is hydrogen and each ofR^(14b), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, —SO₂R¹⁶, and —CO₂R¹⁶. In an even further aspect, R^(14a) ishydrogen and each of R^(14b), R^(14c), R^(14d), and R^(14e) isindependently selected from hydrogen and —SO₂R¹⁶. In a still furtheraspect, R^(14a) is hydrogen and each of R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen and —CO₂R¹⁶.

In a further aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁶and —CO₂R¹⁶. In a still further aspect, R^(14b) is hydrogen and each ofR^(14a), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2dialkylamino, —SO₂R¹⁶ and —CO₂R¹⁶.

In a further aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a stillfurther aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(14b) is hydrogen and each of R^(14a), R^(11b), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen, halogen, C1-C2 alkyl,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylamino. In yet a further aspect, R^(14b) is hydrogen andeach of R^(14a), R^(14c), R^(14d), and R^(14e) is independently selectedfrom hydrogen, —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(14b) is hydrogen and each of R^(14a), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(14b) is hydrogen and each ofR^(14a), R^(14c), R^(14d), and R^(14e) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen and C1-C4alkyl. In a still further aspect, R^(14b) is hydrogen and each ofR^(14a), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a furtheraspect, R^(14b) is hydrogen and each of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, methyl,and ethyl. In an even further aspect, R^(14b) is hydrogen and each ofR^(14a), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen and methyl. In a still further aspect, R^(14b) is hydrogen andeach of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen and ethyl.

In a further aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen andhalogen. In a still further aspect, R^(14b) is hydrogen and each ofR^(14a), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, —F, —Cl, and —Br. In yet a further aspect, R^(14b) is hydrogenand each of R^(14a), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen, —F, and —Cl. In an even further aspect, R^(14b)is hydrogen and each of R^(14a), R^(14c), R^(14d), and R^(14e) isindependently selected from hydrogen and —F. In a still further aspect,R^(14b) is hydrogen and each of R^(14a), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen and —Cl.

In a further aspect, R^(14b) is hydrogen and each of R^(14a), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, —OH, —SH,—CN, —NO₂, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In a still further aspect,R^(14b) is hydrogen and each of R^(14a), R^(14c), R^(14d), and R^(14e)is independently selected from hydrogen, —OH, —SH, —NH₂, —SO₂R¹⁶, and—CO₂R¹⁶. In yet a further aspect, R^(14b) is hydrogen and each ofR^(14a), R^(14c), R^(14d), and R^(14e) is independently selected fromhydrogen, —SO₂R¹⁶, and —CO₂R¹⁶. In an even further aspect, R^(14b) ishydrogen and each of R^(14a), R^(14c), R^(14d), and R^(14e) isindependently selected from hydrogen and —SO₂R¹⁶. In a still furtheraspect, R^(14b) is hydrogen and each of R^(14a), R^(14c), R^(14d), andR^(14e) is independently selected from hydrogen and —CO₂R¹⁶.

In a further aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁶and —CO₂R¹⁶. In a still further aspect, R^(14c) is hydrogen and each ofR^(14a), R^(14b), R^(14d), and R^(14e) is independently selected fromhydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2dialkylamino, —SO₂R¹⁶ and —CO₂R¹⁶.

In a further aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a stillfurther aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen, —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen, halogen,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(14c) is hydrogen and each of R^(14a), R^(14b), R^(14d), and R^(14e)is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2dialkylamino. In yet a further aspect, R^(14c) is hydrogen and each ofR^(14a), R^(14b), R^(14d), and R^(14e) is independently selected fromhydrogen, —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and—N(CH₃)₂.

In a further aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(14c) is hydrogen and each of R^(14a), R^(14b), R^(14d), and R^(14e)is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(14c) is hydrogen and each ofR^(14a), R^(14b), R^(14d), and R^(14e) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen and C1-C4alkyl. In a still further aspect, R^(14c) is hydrogen and each ofR^(14a), R^(14b), R^(14d), and R^(14e) is independently selected fromhydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a furtheraspect, R^(14c) is hydrogen and each of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) is independently selected from hydrogen, methyl,and ethyl. In an even further aspect, R^(14c) is hydrogen and each ofR^(14a), R^(14b), R^(14d), and R^(14e) is independently selected fromhydrogen and methyl. In a still further aspect, R^(14c) is hydrogen andeach of R^(14a), R^(14b), R^(14d), and R^(14e) is independently selectedfrom hydrogen and ethyl.

In a further aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen andhalogen. In a still further aspect, R^(14c) is hydrogen and each ofR^(14a), R^(14b), R^(14d), and R^(14e) is independently selected fromhydrogen, —F, —Cl, and —Br. In yet a further aspect, R^(14c) is hydrogenand each of R^(14a), R^(14b), R^(14d), and R^(14e) is independentlyselected from hydrogen, —F, and —Cl. In an even further aspect, R^(14c)is hydrogen and each of R^(14a), R^(14b), R^(14d), and R^(14e) isindependently selected from hydrogen and —F. In a still further aspect,R^(14c) is hydrogen and each of R^(14a), R^(14b), R^(14d), and R^(14e)is independently selected from hydrogen and —Cl.

In a further aspect, R^(14c) is hydrogen and each of R^(14a), R^(14b),R^(14d), and R^(14e) is independently selected from hydrogen, —OH, —SH,—CN, —NO₂, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In a still further aspect,R^(14c) is hydrogen and each of R^(14a), R^(14b), R^(14d), and R^(14e)is independently selected from hydrogen, —OH, —SH, —NH₂, —SO₂R¹⁶, and—CO₂R¹⁶. In yet a further aspect, R^(14c) is hydrogen and each ofR^(14a), R^(14b), R^(14d), and R^(14e) is independently selected fromhydrogen, —SO₂R¹⁶, and —CO₂R¹⁶. In an even further aspect, R^(14c) ishydrogen and each of R^(14a), R^(14b), R^(14d), and R^(14e) isindependently selected from hydrogen and —SO₂R¹⁶. In a still furtheraspect, R^(14c) is hydrogen and each of R^(14a), R^(14b), R^(14d), andR^(14e) is independently selected from hydrogen and —CO₂R¹⁶.

In a further aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen, halogen,—OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁶and —CO₂R¹⁶. In a still further aspect, R^(14d) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14e) is independently selected fromhydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2dialkylamino, —SO₂R¹⁶ and —CO₂R¹⁶.

In a further aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a stillfurther aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen, —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen, halogen,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(14d) is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14e)is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2dialkylamino. In yet a further aspect, R^(14d) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14e) is independently selected fromhydrogen, —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and—N(CH₃)₂.

In a further aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(14d) is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14e)is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(14d) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14e) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen and C1-C4alkyl. In a still further aspect, R^(14d) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14e) is independently selected fromhydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a furtheraspect, R^(14d) is hydrogen and each of R^(14a), R^(14b), R^(14c), andR^(14e) is independently selected from hydrogen, methyl, and ethyl. Inan even further aspect, R^(14d) is hydrogen and each of R^(14a),R^(14b), R^(14c), and R^(14e) is independently selected from hydrogenand methyl. In a still further aspect, R^(14d) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14e) is independently selected fromhydrogen and ethyl.

In a further aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen andhalogen. In a still further aspect, R^(14d) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14e) is independently selected fromhydrogen, —F, —Cl, and —Br. In yet a further aspect, R^(14d) is hydrogenand each of R^(14a), R^(14b), R^(14c), and R^(14e) is independentlyselected from hydrogen, —F, and —Cl. In an even further aspect, R^(14d)is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14e) isindependently selected from hydrogen and —F. In a still further aspect,R^(14d) is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14e)is independently selected from hydrogen and —Cl.

In a further aspect, R^(14d) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14e) is independently selected from hydrogen, —OH, —SH,—CN, —NO₂, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In a still further aspect,R^(14d) is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14e)is independently selected from hydrogen, —OH, —SH, —NH₂, —SO₂R¹⁶, and—CO₂R¹⁶. In yet a further aspect, R^(14d) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14e) is independently selected fromhydrogen, —SO₂R¹⁶, and —CO₂R¹⁶. In an even further aspect, R^(14d) ishydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14e) isindependently selected from hydrogen and —SO₂R¹⁶. In a still furtheraspect, R^(14d) is hydrogen and each of R^(14a), R^(14b), R^(14c), andR^(14e) is independently selected from hydrogen and —CO₂R¹⁶.

In a further aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen, halogen,—OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁶and —CO₂R¹⁶. In a still further aspect, R^(14e) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14d) is independently selected fromhydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2dialkylamino, —SO₂R¹⁶ and —CO₂R¹⁶.

In a further aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In a stillfurther aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen, halogen,—OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yet afurther aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen, —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen, halogen,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect,R^(14e) is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14d)is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2dialkylamino. In yet a further aspect, R^(14e) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14d) is independently selected fromhydrogen, —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃), and—N(CH₃)₂.

In a further aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen, C1-C4monohaloalkyl, and C1-C4 polyhaloalkyl. In a still further aspect,R^(14e) is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14d)is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2polyhaloalkyl. In yet a further aspect, R^(14e) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14d) is independently is selected fromhydrogen, —CFH₂, —CF₂H, and —CF₃.

In a further aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen and C1-C4alkyl. In a still further aspect, R^(14e) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14d) is independently selected fromhydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a furtheraspect, R^(14e) is hydrogen and each of R^(14a), R^(14b), R^(14c), andR^(14d) is independently selected from hydrogen, methyl, and ethyl. Inan even further aspect, R^(14e) is hydrogen and each of R^(14a),R^(14b), R^(14c), and R^(14d) is independently selected from hydrogenand methyl. In a still further aspect, R^(14e) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14d) is independently selected fromhydrogen and ethyl.

In a further aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen andhalogen. In a still further aspect, R^(14e) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14d) is independently selected fromhydrogen, —F, —Cl, and —Br. In yet a further aspect, R^(14e) is hydrogenand each of R^(14a), R^(14b), R^(14c), and R^(14d) is independentlyselected from hydrogen, —F, and —Cl. In an even further aspect, R^(14e)is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14d) isindependently selected from hydrogen and —F. In a still further aspect,R^(14e) is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14d)is independently selected from hydrogen and —Cl.

In a further aspect, R^(14e) is hydrogen and each of R^(14a), R^(14b),R^(14c), and R^(14d) is independently selected from hydrogen, —OH, —SH,—CN, —NO₂, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In a still further aspect,R^(14e) is hydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14d)is independently selected from hydrogen, —OH, —SH, —NH₂, —SO₂R¹⁶, and—CO₂R¹⁶. In yet a further aspect, R^(14e) is hydrogen and each ofR^(14a), R^(14b), R^(14c), and R^(14d) is independently selected fromhydrogen, —SO₂R¹⁶, and —CO₂R¹⁶. In an even further aspect, R^(14e) ishydrogen and each of R^(14a), R^(14b), R^(14c), and R^(14d) isindependently selected from hydrogen and —SO₂R¹⁶. In a still furtheraspect, R^(14e) is hydrogen and each of R^(14a), R^(14b), R^(14c), andR^(14d) is independently selected from hydrogen and —CO₂R¹⁶.

In a further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are independently selected from halogen, —OH, —SH, —CN,—NO₂, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a stillfurther aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is independently selected from halogen, —OH, —SH, —CN, —NO₂,—NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵.

In a further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect, twoof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen andthree of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) areindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl,C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,and C1-C2 dialkylamino. In yet a further aspect, two of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and three ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from —F, —Cl, —Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H,—CF₃, —OCH₃, —NH(CH₃), and —N(CH₃)₂.

In a further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are independently selected from halogen, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylamino. In a still further aspect, two of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are hydrogen and three of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) are independently selected fromhalogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, two ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and threeof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are independently selected from C1-C4 monohaloalkyl andC1-C4 polyhaloalkyl. In a still further aspect, two of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are hydrogen and three of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) are independently selected fromC1-C2 monohaloalkyl and C1-C2 polyhaloalkyl. In yet a further aspect,two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen andthree of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) areindependently selected from —CFH₂, —CF₂H, and —CF₃.

In a further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are independently selected from C1-C4 alkyl. In a stillfurther aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from methyl, ethyl, iso-propyl, andn-propyl. In yet a further aspect, two of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) are hydrogen and three of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are independently selected from methyl andethyl. In an even further aspect, two of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) are hydrogen and three of R^(14a), R^(14b),R^(14c), R^(14d)and R^(14e) are methyl. In a still further aspect, twoof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen andthree of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are ethyl.

In a further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are independently selected from halogen. In a still furtheraspect, two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) arehydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d) and R^(14e) areindependently selected from —F, —Cl, and —Br. In yet a further aspect,two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen andthree of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) areindependently selected from —F and —Cl. In an even further aspect, twoof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen andthree of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are —F. In astill further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are —Cl. In yet a further aspect, two of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are hydrogen and three of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) are —Br.

In a further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are independently selected from hydrogen, —OH, —SH, —CN,—NO₂, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In a still further aspect, two ofR^(14a), R^(14b), R^(14c), R^(14d) and R^(14e) are hydrogen and three ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are independentlyselected from hydrogen, —OH, —SH, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In yet afurther aspect, two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are hydrogen and three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from hydrogen, —SO₂R¹⁶, and —CO₂R¹⁶.In an even further aspect, two of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are hydrogen and three of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) are independently selected from hydrogen and—SO₂R¹⁶. In a still further aspect, two of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) are hydrogen and three of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are independently selected from hydrogenand —CO₂R¹⁶.

In a further aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from halogen, —OH, —SH, —CN, —NO₂,—NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a stillfurther aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)is independently selected from halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino,C1-C2 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵.

In a further aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from halogen, —OH, —CN, —NO₂, —NH₂,C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylamino. In a still further aspect, threeof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and twoof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl,C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2dialkylamino. In yet a further aspect, three of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are hydrogen and two of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) is independently selected from —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from halogen, C1-C4 alkyl, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylamino. In a still further aspect, three of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are hydrogen and two of R^(14a), R^(14b),R^(14c), R^(14d) and R^(14e) are independently selected from halogen,C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy,C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, threeof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and twoof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from C1-C4 monohaloalkyl and C1-C4polyhaloalkyl. In a still further aspect, three of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are hydrogen and two of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are independently selected from C1-C2monohaloalkyl and C1-C2 polyhaloalkyl. In yet a further aspect, three ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and two ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are independentlyselected from —CFH₂, —CF₂H, and —CF₃.

In a further aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from C1-C4 alkyl. In a still furtheraspect, three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) arehydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d)and R^(14e) areselected from methyl, ethyl, iso-propyl, and n-propyl. In yet a furtheraspect, three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) arehydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) areindependently selected from methyl and ethyl. In an even further aspect,three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogenand two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are methyl.In a still further aspect, three of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are ethyl.

In a further aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from halogen. In a still furtheraspect, three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) arehydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) areindependently selected from —F, —Cl, and —Br. In yet a further aspect,three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogenand two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) areindependently selected from —F and —Cl. In an even further aspect, threeof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and twoof R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are —F. In a stillfurther aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are —Cl. In yet a further aspect, three of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) are —Br.

In a further aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are independently selected from hydrogen, —OH, —SH, —CN, —NO₂,—NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In a still further aspect, three of R^(14a),R^(14b), R^(14c), R^(14d)and R^(14e) are hydrogen and two of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) are independently selected fromhydrogen, —OH, —SH, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. In yet a further aspect,three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogenand two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) areindependently selected from hydrogen, —SO₂R¹⁶, and —CO₂R¹⁶. In an evenfurther aspect, three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are hydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are independently selected from hydrogen and —SO₂R¹⁶. In a still furtheraspect, three of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) arehydrogen and two of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) areindependently selected from hydrogen and —CO₂R¹⁶.

In a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,C1-C4 dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵. In a still further aspect,four of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen andone of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is selected fromhalogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C2 alkyl, C1-C2 alkoxy, C1-C2monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl,C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO₂R¹⁵,and —CO₂R¹⁵.

In a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylamino. In a still further aspect, four of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and one of R^(14a),R^(14b), R^(14c)R^(14d), and R^(14e) is selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2monoalkylamino, and C1-C2 dialkylamino. In yet a further aspect, four ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and one ofR^(14a), R^(14b), R^(14c), R^(14d) and R^(14e) is selected from —F, —Cl,—Br, —OH, —CN, —NO₂, —NH₂, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃, —NH(CH₃),and —N(CH₃)₂.

In a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl,C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino. In astill further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl,C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl,C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino. In yeta further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from —F, —Cl, —Br, —CH₃, —CFH₂, —CF₂H, —CF₃, —OCH₃,—NH(CH₃), and —N(CH₃)₂.

In a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl. Ina still further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl. Inyet a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from —CFH₂, —CF₂H, and —CF₃.

In a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from C1-C4 alkyl. In a still further aspect, four ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and one ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is selected from methyl,ethyl, iso-propyl, and n-propyl. In yet a further aspect, four ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and one ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is selected from methyland ethyl. In an even further aspect, four of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) is methyl. In a still further aspect, four ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and one ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is ethyl.

In a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from halogen. In a still further aspect, four ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and one ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is selected from —F,—Cl, and —Br. In yet a further aspect, four of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) are hydrogen and one of R^(14a), R^(14b),R^(14c), R^(14d), and R^(14e) is selected from —F and —Cl. In an evenfurther aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e)is —F. In a still further aspect, four of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c),R^(14d), and R^(14e) is —Cl. In yet a further aspect, four of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen and one of R^(14a),R^(14b), R^(14c), R^(14d), and R^(14e) is —Br.

In a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from —OH, —SH, —CN, —NO₂, —NH₂, —SO₂R¹⁶ and —CO₂R¹⁶.In a still further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d),and R^(14e) is selected from —OH, —SH, —NH₂, —SO₂R¹⁶, and —CO₂R¹⁶. Inyet a further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is selected from —SO₂R¹⁶ and —CO₂R¹⁶. In an even further aspect,four of R^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) are hydrogen andone of R^(14a), R^(14b), R^(14c), R^(14d) and R^(14e) is —SO₂R¹⁶. In astill further aspect, four of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) are hydrogen and one of R^(14a), R^(14b), R^(14c), R^(14d), andR^(14e) is —CO₂R¹⁶.

d. R¹⁵ Groups

In one aspect, each occurrence of R¹⁵, when present, is independentlyselected from hydrogen, —CH₃, —CFH₂, —CF₂H, —CF₃, —NH₂, —NH(CH₃), and—N(CH₃)₂. In a further aspect, each occurrence of R¹⁵, when present, ishydrogen.

In a further aspect, each occurrence of R¹⁵, when present, isindependently selected from hydrogen and —CH₃. In a still furtheraspect, each occurrence of R¹⁵, when present, is —CH₃.

In a further aspect, each occurrence of R¹⁵, when present, isindependently selected from hydrogen, —CFH₂, —CF₂H, and —CF₃. In a stillfurther aspect, each occurrence of R¹⁵, when present, is independentlyselected from hydrogen, —CFH₂, and —CF₂H. In yet a further aspect, eachoccurrence of R¹⁵, when present, is independently selected from hydrogenand —CFH₂. In an even further aspect, each occurrence of R¹⁵, whenpresent, is —CF₃. In a still further aspect, each occurrence of R¹⁵,when present, is —CF₂H. In yet a further aspect, each occurrence of R¹⁵,when present, is —CFH₂.

In a further aspect, each occurrence of R¹⁵, when present, isindependently selected from hydrogen, —NH₂, —NH(CH₃), and —N(CH₃)₂. In astill further aspect, each occurrence of R¹⁵, when present, isindependently selected from hydrogen, —NH₂, and —NH(CH₃). In yet afurther aspect, each occurrence of R¹⁵, when present, is independentlyselected from hydrogen and —NH₂. In an even further aspect, eachoccurrence of R¹⁵, when present, is —N(CH₃)₂. In a still further aspect,each occurrence of R¹⁵, when present, is —NH(CH₃). In yet a furtheraspect, each occurrence of R¹⁵, when present, is —NH₂.

e. R¹⁶ Groups

In one aspect, each occurrence of R¹⁶, when present, is independentlyselected from hydrogen, —CH₃, —CFH₂, —CF₂H, —CF₃, —NH₂, —NH(CH₃), and—N(CH₃)₂. In a further aspect, each occurrence of R¹⁶, when present, ishydrogen.

In a further aspect, each occurrence of R¹⁶, when present, isindependently selected from hydrogen and —CH₃. In a still furtheraspect, each occurrence of R¹⁶, when present, is —CH₃.

In a further aspect, each occurrence of R¹⁶, when present, isindependently selected from hydrogen, —CFH₂, —CF₂H, and —CF₃. In a stillfurther aspect, each occurrence of R¹⁶, when present, is independentlyselected from hydrogen, —CFH₂, and —CF₂H. In yet a further aspect, eachoccurrence of R¹⁶, when present, is independently selected from hydrogenand —CFH₂. In an even further aspect, each occurrence of R¹⁶, whenpresent, is —CF₃. In a still further aspect, each occurrence of R¹⁶,when present, is —CF₂H. In yet a further aspect, each occurrence of R¹⁶,when present, is —CFH₂.

In a further aspect, each occurrence of R¹⁶, when present, isindependently selected from hydrogen, —NH₂, —NH(CH₃), and —N(CH₃)₂. In astill further aspect, each occurrence of R¹⁶, when present, isindependently selected from hydrogen, —NH₂, and —NH(CH₃). In yet afurther aspect, each occurrence of R¹⁶, when present, is independentlyselected from hydrogen and —NH₂. In an even further aspect, eachoccurrence of R¹⁶, when present, is —N(CH₃)₂. In a still further aspect,each occurrence of R¹⁶, when present, is —NH(CH₃). In yet a furtheraspect, each occurrence of R¹⁶, when present, is —NH₂.

4. Other CDK2 Inhibitors

In one aspect, disclosed are CDK2 inhibitors having a structurerepresented by a formula:

wherein R²⁰ is selected from —SO₂R^(20a), —OH, NH₂, substituted amide,C1-C4 alkyl carbonyl, C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl,and C1-C8 alkyl and is substituted with 0, 1, or 2 groups independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;wherein each of R²¹, R²³, and R²⁵ is independently selected fromhydrogen, halogen, —OH, NH₂, C1-C4 monoalkylamino, C1-C4dialkylaminomethyl, and C1-C8 alkyl and is independently substitutedwith 0, 1, or 2 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein each of R²²and R²⁴ is independently selected from hydrogen and C1-C8 alkyl and isindependently substituted with 0, 1, or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl, or apharmaceutically acceptable salt thereof.

For example, a CDK2 inhibitor can have a structure represented by aformula:

wherein R^(20a) is selected from —OH, NH₂, C1-C4 monoalkylamino, C1-C4dialkylaminomethyl, and C1-C8 alkyl and is substituted with 0, 1, or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl; wherein each of R²¹, R²³, and R²⁵ is independentlyselected from hydrogen, halogen, —OH, NH₂, C1-C4 monoalkylamino, C1-C4dialkylaminomethyl, and C1-C8 alkyl and is independently substitutedwith 0, 1, or 2 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein each of R²²and R²⁴ is independently selected from hydrogen and C1-C8 alkyl and isindependently substituted with 0, 1, or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl, or apharmaceutically acceptable salt thereof.

In one aspect, a CDK2 inhibitor is provided as a compound having theformula:

This compound is a potent inhibitor of CDK1/2/9 with IC50 of 16 nM/6nM/20 nM. This compound has high oral bioavailability, F=91%.

a. R²⁰ Groups

In one aspect, each occurrence of R²⁰, when present, is selected from—OH, NH₂, C1-C4 monoalkylamino (e.g., methylamino, ethylamino,propylamino, or butylamino), C1-C4 dialkylaminomethyl (e.g.,dimethylamino, methylethylamino, methylpropylamino, methylbutylamino,diethylamino, ethylpropylamino, ethylbutylamino, dipropylamino,propylbutylamino, or dibutylamino), and C1-C8 alkyl (e.g., methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl). As an example,C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2alkyl.

In a further aspect, each occurrence of R^(20a) can be selected from—OH, NH₂, C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8alkyl.

In a further aspect, each occurrence of R²⁰ and R^(20a) can besubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl.

b. R²¹ Groups

In one aspect, each occurrence of R²¹, when present, is selected fromhydrogen, halogen (e.g., fluoride, chloride, bromide, or iodide), —OH,NH₂, C1-C4 monoalkylamino (e.g., methylamino, ethylamino, propylamino,or butylamino), C1-C4 dialkylaminomethyl (e.g., dimethylamino,methylethylamino, methylpropylamino, methylbutylamino, diethylamino,ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, ordibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can beselected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R²¹ can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

c. R²² Groups

In one aspect, each occurrence of R²², when present, is selected fromhydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can be selected tobe C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R²² can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

d. R²³ Groups

In one aspect, each occurrence of R²³, when present, is selected fromhydrogen, halogen (e.g., fluoride, chloride, bromide, or iodide), —OH,NH₂, C1-C4 monoalkylamino (e.g., methylamino, ethylamino, propylamino,or butylamino), C1-C4 dialkylaminomethyl (e.g., dimethylamino,methylethylamino, methylpropylamino, methylbutylamino, diethylamino,ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, ordibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can beselected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R²³ can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

e. R²⁴ Groups

In one aspect, each occurrence of R²⁴, when present, is selected fromhydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can be selected tobe C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R²⁴ can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

f. R²⁵ Groups

In one aspect, each occurrence of R²⁵, when present, is selected fromhydrogen, halogen (e.g., fluoride, chloride, bromide, or iodide), —OH,NH₂, C1-C4 monoalkylamino (e.g., methylamino, ethylamino, propylamino,or butylamino), C1-C4 dialkylaminomethyl (e.g., dimethylamino,methylethylamino, methylpropylamino, methylbutylamino, diethylamino,ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, ordibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can beselected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R²⁵ can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

In one aspect, disclosed are CDK2 inhibitors having a structurerepresented by a formula:

wherein each occurrence of R³⁰ is independently selected fromsubstituted phenyl, C1-C8 alkyl, carbocyclic, substituted cyclohexyl,piperidine wherein each of R³¹, R³², and R³³ is independently selectedfrom hydrogen and C1-C8 alkyl and is independently substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl; and wherein R³⁴ is selected from hydroxyalkyl, substituted or unsubstituted phenyl, substituted or unsubstitutedbenzyl or a pharmaceutically acceptable salt thereof.

In a further aspect, disclosed are CDK2 inhibitors having a structurerepresented by a formula:

wherein each occurrence of X is independently a halogen (e.g., fluoride,chloride, bromide, or iodide), wherein each of R³⁰, R³¹, R³², and R³³ isindependently selected from hydrogen and C1-C8 alkyl and isindependently substituted with 0, 1, or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; andwherein R³⁴ is selected from —OH, NH₂, C1-C4 monoalkylamino, C1-C4dialkylaminomethyl, and C1-C8 alkyl and is substituted with 0, 1, or 2groups independently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl, or a pharmaceutically acceptable salt thereof.

In one aspect, a CDK2 inhibitor is provided as a compound having theformula:

This compound is a multi-CDK inhibitor for CDK1, 2, 4, 6 and 9 with IC50of 10-210 nM. In certain aspects, this compound can have a low oralbioavailability (<1%). This compound is a potent cell cycle inhibitorand can be useful for the treatment of chronic lymphocytic leukemia andfor the treatment of mantle cell lymphoma.

g. R³⁰ Groups

In one aspect, each occurrence of R³⁰, when present, is selected fromhydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can be selected tobe C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R³⁰ can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

h. R³¹ Groups

In one aspect, each occurrence of R³¹, when present, is selected fromhydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can be selected tobe C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R³¹ can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

i. R³² Groups

In one aspect, each occurrence of R³², when present, is selected fromhydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can be selected tobe C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R³² can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

j. R³³ Groups

In one aspect, each occurrence of R³³, when present, is selected fromhydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, or octyl). As an example, C1-C8 alkyl can be selected tobe C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.

In a further aspect, each occurrence of R³³ can be substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl.

k. R³⁴ Groups

In one aspect, each occurrence of R³⁰ is independently selected fromsubstituted phenyl, C1-C8 alkyl, carbocyclic, substituted cyclohexyl,piperidine wherein each of R³¹, R³² and R³³ is independently selectedfrom hydrogen and C1-C8 alkyl and is independently substituted with 0,1, or 2 groups independently selected from halogen, —OH, —CN, —NO₂,—NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,and C1-C4 dialkylaminomethyl; and wherein R³⁴ is selected from hydroxyalkyl, substituted or unsubstituted phenyl, substituted or unsubstitutedbenzyl or a pharmaceutically acceptable salt thereof.

In a further aspect, each occurrence of R^(34a), when present, isselected from —OH, NH₂, C1-C4 monoalkylamino (e.g., methylamino,ethylamino, propylamino, or butylamino), C1-C4 dialkylaminomethyl (e.g.,dimethylamino, methylethylamino, methylpropylamino, methylbutylamino,diethylamino, ethylpropylamino, ethylbutylamino, dipropylamino,propylbutylamino, or dibutylamino), and C1-C8 alkyl (e.g., methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl). As an example,C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2alkyl.

In a further aspect, each occurrence of R³⁴ and R^(34a) can besubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl.

Explant Explant Therapeutic Compound HEI-OC1 Cisplatin Cisplatin Index(Scaffold) IC50 (nM) LD50 (nM) LD50 (n/M) LD50/IC50 SJZuo-4 Kenpaullone(Paullone)

2100  150 >30,000 >200 SJZuo-19 AZD5438 (Pyrimidine)

 ~25  <1,000  <40 SJZuo-20 AT7519 (Pyrazole)

 380  ~25  <1,000  <40 SJZuo-12 CDK2 inhibitor II (Indole)

 500 1,000 >12,000 12 SJZuo-9 Olomoucine II (Purine)

 800 3,000 >33,000 11

5. Example Compounds

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

C. Methods of Making a Compound

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, asdescribed and exemplified below. In certain specific examples, thedisclosed compounds can be prepared by Route I and Route II, asdescribed and exemplified below. The following examples are provided sothat the invention might be more fully understood, are illustrativeonly, and should not be construed as limiting.

1. Route I

In one aspect, paullone derivatives can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 1.3, and similar compounds, can beprepared according to reaction Scheme 1B above. Thus, compounds of type1.6 can be prepared by a cyclization reaction (e.g., Fischer indolereaction) of an appropriate hydrazine, e.g., 1.4 as shown above, with anappropriate benzazepine, e.g., 1.5 as shown above. Appropriatehydrazines and appropriate benzazepines are commercially available orprepared by methods known to one skilled in the art. The cyclizationreaction is carried out in the presence of an appropriate base, e.g.,sodium acetate, in an appropriate protic solvent, e.g., acetic acid, atan appropriate temperature, e.g., 70° C., for an appropriate period oftime, e.g., 1 hour. As can be appreciated by one skilled in the art, theabove reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 1.1 and 1.2), can be substitutedin the reaction to provide paullone derivatives similar to Formula 1.3.

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

2. Route II

In one aspect, purine derivatives can be prepared as shown below.

Compounds are represented in generic form, wherein X is a halogen, andother substituents are as noted in compound descriptions elsewhereherein. A more specific example is set forth below.

In one aspect, compounds of type 2.7, and similar compounds, can beprepared according to reaction Scheme 2B above. Thus, compounds of type2.9 can be prepared by a substitution reaction of an appropriate arylhalide, e.g., 2.7 as shown above. Appropriate aryl halides arecommercially available or prepared by methods known to one skilled inthe art. The substitution reaction is carried out in the presence of anappropriate amine, e.g., 2.8 as shown above, in an appropriate solvent,e.g., ethanol. Compounds of type 2.11 can be prepared an alkylationreaction of an appropriate amine, e.g., 2.9 as shown above. Thealkylation reaction is carried out in the presence of an appropriatealkyl halide, e.g., 2.10, and an appropriate base, e.g., potassiumcarbonate, in an appropriate solvent, e.g., dimethylsulfoxide. Compoundsof type 2.13 can be prepared by a substitution reaction of anappropriate aryl halide, e.g., 2.11 as shown above. The substitutionreaction is carried out in the presence of an appropriate amine, e.g.,2.12 as shown above, in an appropriate solvent, e.g., ethanol. As can beappreciated by one skilled in the art, the above reaction provides anexample of a generalized approach wherein compounds similar in structureto the specific reactants above (compounds similar to compounds of type2.1, 2.2, 2.3, 2.4, 2.5, and 2.6), can be substituted in the reaction toprovide purine derivatives similar to Formula 2.7.

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

3. Route III

In one aspect, purine derivatives can be prepared as shown below.

Compounds are represented in generic form, wherein each of X¹ and X² areindependently halogen, and where substituents are as noted in compounddescriptions elsewhere herein. A more specific example is set forthbelow.

In one aspect, compounds of type 3.5, and similar compounds, can beprepared according to reaction Scheme 3B above. Thus, compounds of type3.8 can be prepared by a displacement reaction of an appropriate guaninederivative, e.g., 3.6 as shown above. Appropriate guanine derivativesare commercially available or prepared by methods known to one skilledin the art. The displacement reaction is carried out in the presence ofan appropriate acetate, e.g., 3.7 as shown above, and an appropriatebase, e.g., 1,8-diazobicyclo[5.4.0] undec-7-ene (DBU), in an appropriatesolvent, e.g., acetonitrile, at an appropriate temperature, e.g., 0° C.,for an appropriate period of time, e.g., thirty minutes. Compounds oftype 3.10 can be prepared by an alkylation reaction of an appropriateamine, e.g., 3.8 as shown above. The alkylation reaction is carried outin the presence of an appropriate alkyl halide, e.g., 3.9 as shownabove, and an appropriate base, e.g., potassium carbonate, in anappropriate solvent, e.g., dimethylsulfoxide. As can be appreciated byone skilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 3.1,3.2, 3.3, and 3.4), can be substituted in the reaction to providepara-substituted arenes similar to Formula 3.5.

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

4. Route IV

In one aspect, purine derivatives can be prepared as shown below.

Compounds are represented in generic form, where substituents are asnoted in compound descriptions elsewhere herein. A more specific exampleis set forth below.

In one aspect, compounds of type 4.9, and similar compounds, can beprepared according to reaction Scheme 4B above. Thus, compounds of type4.1 can be prepared by protection of an appropriate purine derivative,e.g., 3.6 as shown above. Appropriate purine derivatives arecommercially available or prepared by methods known to one skilled inthe art. The protection is carried out in the presence of an appropriateprotecting group, e.g., di-tert-butyldicarbonate as shown above, and anappropriate catalytic base, e.g., DMAP as shown above, in an appropriatesolvent, e.g., dimethylsulfoxide, at an appropriate temperature, e.g.,0° C. The reaction is then warmed to an appropriate temperature, e.g.,room temperature, over a period of time sufficient to allow the reactionto proceed, e.g., 2 hours. Compounds of type 4.2 can be prepared byprotection of an appropriate amine, e.g., 4.1 as shown above. Theprotection is carried out in the presence of an appropriate base, e.g.,sodium hydride, in an appropriate solvent, e.g., tetrahydrofuran.Compounds of type 4.11 can be prepared by a displacement reaction of anappropriate amine, e.g., 4.2 as shown above. The displacement reactionis carried out in the presence of an appropriate alcohol, e.g., 4.10 asshown above, and an appropriate nucleophile, e.g., triphenylphosphine,followed by the addition of an appropriate azodicarboxylate, e.g.,diisopropyl azodicarboxylate. Compounds of type 4.13 can be prepared bya displacement reaction of an appropriate amine, e.g., 4.11 as shownabove. The displacement reaction is carried out in the presence of anappropriate alcohol, e.g., 4.12 as shown above, and an appropriatenucleophile, e.g., triphenylphosphine, followed by the addition of anappropriate azodicarboxylate, e.g., diisopropyl azodicarboxylate.Compounds of type 4.15 can be prepared by a displacement reaction of anappropriate halide, e.g., 4.13 as shown above. The displacement reactionis carried out in the presence of an appropriate alcohol, e.g., 4.14 asshown above, and an appropriate nucleophile, e.g., triphenylphosphine,followed by the addition of an appropriate azodicarboxylate, e.g.,diisopropyl azodicarboxylate. Compounds of type 4.16 can be prepared bydeprotection of an appropriate amine, e.g., 4.15 as shown above. Thedeprotection is carried out in the presence of an appropriate acid,e.g., trifluoroacetic acid. As can be appreciated by one skilled in theart, the above reaction provides an example of a generalized approachwherein compounds similar in structure to the specific reactants above(compounds similar to compounds of type 3.6, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, and 4.8), can be substituted in the reaction to provide purinederivatives similar to Formula 4.9.

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

5. Route V

In one aspect, 3-(2-phenylhydrazono)indolin-2-one derivatives can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 5.3, and similar compounds, can beprepared according to reaction Scheme 5B above. Thus, compounds of type5.6 can be prepared by a hydrolysis reaction of an appropriatehydrazone, e.g., 5.4 as shown above. Appropriate hydrazones arecommercially available or prepared by methods known to one skilled inthe art. The hydrolysis reaction is carried out in the presence of anappropriate hydrazine, e.g., 5.5 as shown above, which are commerciallyavailable or prepared by methods known to one skilled in the art, in anappropriate solvent, e.g., ethanol, at an appropriate temperature, e.g.,refluxing conditions, for an appropriate period of time, e.g., 16 hours.As can be appreciated by one skilled in the art, the above reactionprovides an example of a generalized approach wherein compounds similarin structure to the specific reactants above (compounds similar tocompounds of type 5.1 and 5.2), can be substituted in the reaction toprovide 3-(2-phenylhydrazono)indolin-2-one derivatives similar toFormula 5.3.

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

6. Route VI

In one aspect, 4-(1H-imidazol-5-yl)-N-(phenyl)pyrimidin-2-aminederivatives can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 6.3, and similar compounds, can beprepared according to reaction Scheme 6B above. Thus, compounds of type6.6 can be prepared by a coupling reaction between appropriate arylhalide and amino pyrimidines, e.g., 6.4 and 6.5 respectively as shownabove. Appropriate aryl halides are commercially available or preparedby methods known to one skilled in the art. The coupling reaction iscarried out in the presence of an appropriate imidazoyl pyrimidines,e.g., 6.5 as shown above, which are commercially available or preparedby methods known to one skilled in the art, in an appropriate solvent,e.g., dioxane, at an appropriate temperature, e.g., refluxingconditions, for an appropriate period of time, e.g., 16 hours. As can beappreciated by one skilled in the art, the above reaction provides anexample of a generalized approach wherein compounds similar in structureto the specific reactants above (compounds similar to compounds of type6.1 and 6.2), can be substituted in the reaction to provide4-(1H-imidazol-5-yl)-N-(phenyl)pyrimidin-2-amine derivatives similar toFormula 6.3.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

D. Pharmaceutical Compositions

In one aspect, disclosed are pharmaceutical compositions comprising aCDK2 inhibitor, or a pharmaceutically acceptable salt thereof; and oneor more of: (a) at least one agent known to treat hearing impairment, ora pharmaceutically acceptable salt thereof; and (b) at least one agentknown to prevent hearing impairment, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier.

In one aspect, disclosed are pharmaceutical compositions comprising acompound selected from:

or a pharmaceutically acceptable salt thereof; and one or more of: atleast one agent known to treat hearing impairment, or a pharmaceuticallyacceptable salt thereof; at least one agent known to prevent hearingimpairment, or a pharmaceutically acceptable salt thereof; wherein atleast one is present in an effective amount; and a pharmaceuticallyacceptable carrier.

In one aspect, disclosed are pharmaceutical compositions comprising acompound selected from:

or a pharmaceutically acceptable salt thereof; and one or more of: (a)at least one agent known to treat hearing impairment, or apharmaceutically acceptable salt thereof; and (b) at least one agentknown to prevent hearing impairment, or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier.

In various aspects, the compounds and compositions of the invention canbe administered in pharmaceutical compositions, which are formulatedaccording to the intended method of administration. The compounds andcompositions described herein can be formulated in a conventional mannerusing one or more physiologically acceptable carriers or excipients. Forexample, a pharmaceutical composition can be formulated for local orsystemic administration, e.g., administration by drops or injection intothe ear, insufflation (such as into the ear), intravenous, topical, ororal administration.

The nature of the pharmaceutical compositions for administration isdependent on the mode of administration and can readily be determined byone of ordinary skill in the art. In various aspects, the pharmaceuticalcomposition is sterile or sterilizable. The therapeutic compositionsfeatured in the invention can contain carriers or excipients, many ofwhich are known to skilled artisans. Excipients that can be used includebuffers (for example, citrate buffer, phosphate buffer, acetate buffer,and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid,phospholipids, polypeptides (for example, serum albumin), EDTA, sodiumchloride, liposomes, mannitol, sorbitol, water, and glycerol. Thenucleic acids, polypeptides, small molecules, and other modulatorycompounds featured in the invention can be administered by any standardroute of administration. For example, administration can be parenteral,intravenous, subcutaneous, or oral. A modulatory compound can beformulated in various ways, according to the corresponding route ofadministration. For example, liquid solutions can be made foradministration by drops into the ear, for injection, or for ingestion;gels or powders can be made for ingestion or topical application.Methods for making such formulations are well known and can be found in,for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro,ed., Mack Publishing Co., Easton, Pa. 1990.

In various aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In various aspects, the pharmaceutical compositions of this inventioncan include a pharmaceutically acceptable carrier and a compound or apharmaceutically acceptable salt of the compounds of the invention. Thecompounds of the invention, or pharmaceutically acceptable saltsthereof, can also be included in pharmaceutical compositions incombination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In a further aspect, the CDK2 inhibitor is selected from a paullonederivative, a purine derivative, and a3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceuticallyacceptable salt thereof. In a still further aspect, the CDK2 inhibitoris selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, an effective amount is a therapeutically effectiveamount. In a still further aspect, an effective amount is aprophylactically effective amount.

In a further aspect, the pharmaceutical composition is administered to amammal. In a still further aspect, the mammal is a human. In an evenfurther aspect, the human is a patient.

In a further aspect, the agent known to treat hearing impairment isselected from an antiepileptic drug blocking T-type calcium channels; ananticonvulsant; a synthetic glucocorticoid; a loop diuretic; ananti-oxidant; a proton pump inhibitor; a PDE5 inhibitor; and a mGluR7inhibitor. In a still further aspect, the agent known to treat a hearingimpairment is selected from trimethadione; mibefrabil; ethosuximide;3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide(TTA-P2); NNC 55-0396; ML 218; nilvadipine; valproic acid;oxcarbazepine; phenobarbital; phenytoin; zonisamide; nicardipine;chlordiazepoxide; sipatrigine; halothane; octanol; pimozide;penfluridol; fluspirilene; thioridazine; clozapine; haloperidol;tetramethrin; tetrandrine; amiodarone; bepridil; cinnarizine;flunarizine; amiloride; anandamide; dexamethasone; methylprednisolone;N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide;2-phenyl-1,2-benzisoselenazol-3-one (ebselen); sodium thiosulfate;D-methionine; furosemide; N-acetyl-L-cysteine; vitamin A; vitamin C;vitamin E; vigabatrin; omeprazole; lansoprazole; pantoprazole;rabeprazole; esomerprazole; pariprazole; leminoprazole;3,3′-diindolylmethane; vardenafil; sildenafil; tadalafil; udenafil;dasantafil; avanafil; SLx2101; LAS34179;N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride;R(+)-N-propargyl-1-aminoindan; and L-carnitine.

In a further aspect, the chemotherapeutic agent is selected from aplatinum-based agent. In a still further aspect, the platinum-basedagent is selected from carboplatin, cisplatin, transplatin, nedaplatin,oxaliplatin, picoplatin, satraplatin, transplatin, and triplatin. In yeta further aspect, the platinum-based agent is cisplatin.

In a further aspect, the ototoxic agent is selected from one or more ofan antibiotic, a loop diuretic, an antimetabilite, and a salicyclate. Ina still further aspect, the antibiotic agent is selected from one ormore of daunorubicin, doxorubicin, epirubicin, idarubicin,actinomycin-D, bleomycin, and mitomycin-C, or a pharmaceuticallyacceptable salt thereof. In yet a further aspect, the antibiotic agentis an aminoglycoside. In an even further aspect, the aminoglycoside isselected from one or more of amikacin, apramycin, arbekacin, astromicin,bekanamycin, dibekacin, framycetin, gentamicin, hygromycin B,isepamicin, kanamycin, neomycin, netilmicin, paromomycin,rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin,tobramycin, and verdamicin, or a pharmaceutically acceptable saltthereof.

In a further aspect, the loop diuretic is selected from one or more offurosemide; ethacrynic acid; or bumetanide, or a pharmaceuticallyacceptable salt thereof.

In a further aspect, the antimetabilite is selected one or more of ananti-folate, a fluoropyridimidine, a deoxynucleoside analogue, and athiopurine. In a still further aspect, the antimetabolite is selectedfrom one or more of methotrexate, pemetrexed, fluorouracil,capecitabine, cytarabine, gemcitabine, decitabine, 5-azacytidine,fludarabine, nelarabine, cladribine, clofarabine, pentostatin,thioguanine, and mercaptopurine, or a pharmaceutically acceptable saltthereof.

In a further aspect, the salicylate is selected from one or more ofsalicylic acid, methyl salicylate, and trolamine salicylate, orpharmaceutically acceptable salts thereof.

In a further aspect, the agent known to prevent hearing impairment isselected from one or more of fish oil, an omega-3 fatty acid, magnesium,folic acid, vitamin A, vitamin C, vitamin E, rebamipide, alpha-lipoicacid, N-acetylcysteine (NAC), Elselen, D-methionine, magnesium, ABCmagnesium (vitamins A, B, and C, plus magnesium). Molecular hydrogen(hydrogen-rich water), dexamethasone, Acuval, CoQ10, L-arginine, Ginkobiloba, coenzyme Q10, Z-VAD-fmk, thymidylate kinase (TMK, AM111),retinoic acid, calcium, calcineurin inhibitors, or a pharmaceuticallyacceptable salt thereof.

In a further aspect, the pharmaceutical composition is used to treathearing impairment.

In a further aspect, the pharmaceutical composition is used to prevent ahearing impairment.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

E. Methods of Preparing a Composition

In one aspect, disclosed are methods of preparing a pharmaceuticalcomposition, the method comprising the step of combining a CDK2inhibitor, or a pharmaceutically acceptable salt thereof; and one ormore of: (a) at least one agent known to treat hearing impairment, or apharmaceutically acceptable salt thereof; (b) at least one agent knownto prevent hearing impairment, or a pharmaceutically acceptable saltthereof; wherein at least one is present in an effective amount; and apharmaceutically acceptable carrier. In a further aspect, the effectiveamount is a prophylactically effective amount. In a still furtheraspect, the effective amount is a therapeutically effective amount.

In one aspect, disclosed are methods of preparing a pharmaceuticalcomposition, the method comprising the step of combining a compoundselected from:

or a pharmaceutically acceptable salt thereof; and one or more of: atleast one agent known to treat hearing impairment, or a pharmaceuticallyacceptable salt thereof; at least one agent known to prevent hearingimpairment, or a pharmaceutically acceptable salt thereof, wherein atleast one is present in an effective amount; and a pharmaceuticallyacceptable carrier.

In one aspect, disclosed are methods of preparing a pharmaceuticalcomposition, the method comprising the step of combining a compoundselected from:

or a pharmaceutically acceptable salt thereof; and one or more of: (a)at least one agent known to treat hearing impairment, or apharmaceutically acceptable salt thereof; (b) at least one agent knownto prevent hearing impairment, or a pharmaceutically acceptable saltthereof; wherein at least one is present in an effective amount; and apharmaceutically acceptable carrier.

In a further aspect, the CDK2 inhibitor is selected from a paullonederivative, a purine derivative, and a3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceuticallyacceptable salt thereof. In a still further aspect, the CDK2 inhibitoris selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, an effective amount is a therapeutically effectiveamount. In a still further aspect, an effective amount is aprophylactically effective amount.

In a further aspect, combining is co-formulation of the CDK2 inhibitor,the agent known to treat hearing impairment and/or the agent known toprevent hearing impairment with the pharmaceutically acceptable carrier.In a still further aspect, co-formulation is an oral solid dosage formcomprising the CDK2 inhibitor, the agent known to treat hearingimpairment, and/or the agent known to prevent hearing impairment, andthe pharmaceutically acceptable carrier. In yet a further aspect, thesolid dosage form is a tablet. In an even further aspect, the soliddosage dorm is a capsule.

In a further aspect, co-formulation is an inhaled dosage form comprisingthe CDK2 inhibitor, the agent known to treat hearing impairment, and/orthe agent known to prevent hearing impairment, and the pharmaceuticallyacceptable carrier.

In a further aspect, co-formulation is an injectable dosage formcomprising the CDK2 inhibitor, the agent known to treat hearingimpairment, and/or the agent known to prevent hearing impairment, andthe pharmaceutically acceptable carrier.

In a further aspect, the pharmaceutical composition is used to treathearing impairment. In a further aspect, the pharmaceutical compositionis used to prevent hearing impairment.

F. Methods of Treating Hearing Impairment

In one aspect, disclosed are methods of treating hearing impairmentcomprising administering to a subject diagnosed with a need fortreatment of hearing impairment a therapeutically effective amount of acyclin-dependent kinase 2 (CDK2) inhibitor, or a pharmaceuticallyacceptable salt thereof.

In one aspect, disclosed are methods of treating hearing impairment, themethod comprising administering to a subject diagnosed with a need fortreatment of hearing impairment a therapeutically effective amount of acompound selected from:

or a pharmaceutically acceptable salt thereof.

In one aspect, disclosed are methods of treating hearing impairment, themethod comprising administering to a subject diagnosed with a need fortreatment of hearing impairment a therapeutically effective amount of acompound selected from:

or a pharmaceutically acceptable salt thereof.

In various aspects, the compounds and compositions disclosed herein areuseful for treating, preventing, ameliorating, controlling or reducingthe risk of a variety of hearing impairments and disorders, includinghearing loss, deafness, tinnitus, ringing, Presbyacusis, auditoryneuropathy, acoustic trauma, acoustic neuroma, Pendred syndrome, Ushersyndrome, Wardenburg syndrome, non-syndromic sensorineural deafness,otitis media, otosclerosis, Meniere's disease, ototoxicity,labyrinthitis, as well as hearing impairments caused by infection (i.e.,measles, mumps, or meningitis), medicines such as antibiotics, and somecancer treatments (i.e., chemotherapy and radiation therapy).

Noise-induced hearing loss (NIHL) caused by intense or constant noiseexposure is irreversible, resulting in a permanent disability tomilitary personnel. NIHL is the No. 1 diagnosis among U.S. soldiers whoserved in Afghanistan(http://issuu.com/hearinghealthmagazine/docs/hearinghealthwinter2010issuurev3).Of 1,250 Marine Commandos who served in Afghanistan, 69% sufferedhearing loss due to the intense noise of combat. Hearing impairmentsignificantly affects performance (Consideration of Hazardous Noise inthe Acquisition of Selected Major Department of the Navy Weapon Systemsand Platforms N2010-0038, 22 Jun. 2010). Given the importance ofauditory acuity in perceiving commands and sensing enemy activity, it isclear that even mild loss of hearing increases the risk to soldiers.While hearing aids and cochlear implants are helpful devices in thecivilian and non-combatant community, they are not an appropriate remedyin a combat setting. When hearing loss restricts continued militaryservice, forces suffer loss of personnel, often including the mosteffective and experienced officers and non-commissioned officers (NCOs).Finally, even the best available protection cannot prevent NIHL. As aresult, 2.3 million veterans now receive disability compensation andtreatment that exceeds $2 billion annually (Annual Benefits ReportFiscal Year 2012, U.S. Dept. Veterans Affairs). Among veterans whosuffer from NIHL, difficulty in communicating with clinicians and familyimpedes reintegration into society and exacerbates depression andanxiety. A preventive solution would cost-effectively and significantlyimprove the effectiveness of military personnel and the quality of lifeof veterans.

Traumatic brain injury (TBI) and blast-associated injury occur mostfrequently in military situations where blast exposure cannot bepredicted, trauma intensity exceeds the effectiveness of protectivedevices, or protective devices are not available. TBI is oftenaccompanied by a diverse range of disruption or damage to the auditorysensory system, which is highly vulnerable to blast injury. Extremephysical blast force can cause damage of various types to the peripheralauditory system, including rupture of the tympanic membrane (TM,eardrum), fracture of the middle ear bones, dislocation of sensory haircells from the basilar membrane, and loss of spiral ganglia thatinnervate hair cells. In human studies of blast injury, approximately17-29% of cases involve severe TM rupture, while 33-78% involve moderateto severe sensorineural hearing loss (hair cell and ganglion loss).Therefore, TBI and blast injury are a common, although extreme, cause ofhearing loss.

In various aspects, the disclosed compounds can be used in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of hearing impairments and disordersfor which disclosed compounds or the other drugs can have utility, wherethe combination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) can be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and a disclosed compound is preferred. However, thecombination therapy can also include therapies in which a disclosedcompound and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the disclosedcompounds and the other active ingredients can be used in lower dosesthan when each is used singly. Accordingly, the pharmaceuticalcompositions include those that contain one or more other activeingredients, in addition to a compound of the present invention.

Where appropriate, following treatment, the subject (e.g., human orother animal) can be tested for an improvement in hearing or in othersymptoms related to hearing disorders. Methods for measuring hearing arewell-known and include pure tone audiometry, air conduction, and boneconduction tests. These exams measure the limits of loudness (intensity)and pitch (frequency) that a human can hear. Hearing tests in humansinclude behavioral observation audiometry (for infants to seven months),visual reinforcement orientation audiometry (for children 7 months to 3years) and play audiometry for children older than 3 years. Oto-acousticemission testing can be used to test the functioning of the cochlearhair cells, and electro-cochleography provides information about thefunctioning of the cochlea and the first part of the nerve pathway tothe brain. In various aspects, treatment can be continued with orwithout modification or can be stopped.

In a further aspect, the CDK2 inhibitor is selected from a paullonederivative, a purine derivative, and a3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceuticallyacceptable salt thereof. In a still further aspect, the CDK2 inhibitoris selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the subject is a mammal. In a still further aspect,the mammal is human.

In a further aspect, the subject has been diagnosed with a need fortreatment of a hearing impairment prior to the administering step. In astill further aspect, the subject is at risk for developing a hearingimpairment prior to the administering step.

In a further aspect, the CDK2 inhibitor is administered locally. In astill further aspect, the CDK2 inhibitor is administered systemically.In yet a further aspect, the CDK2 inhibitor is administered locally tothe inner ear of the subject. In an even further aspect, the CDK2inhibitor is administered via injection into one or more of the scalatympani, cochlear duct, scala vestibule of the cochlea, into theauditory nerve trunk in the internal auditory meatus, or into the middleear space across the transtympanic membrane/ear drum.

In a further aspect, the CDK2 inhibitor is administered in an amount offrom about 0.001 μM to about 1.0×10⁴ μM. In a still further aspect, theCDK2 inhibitor is administered in an amount of from about 0.001 μM toabout 1.0×10² μM. In yet a further aspect, the CDK2 inhibitor isadministered in an amount of from about 0.001 μM to about 10 μM. In aneven further aspect, the CDK2 inhibitor is administered in an amount offrom about 0.01 μM to about 1.0×10⁴ μM. In a still further aspect, theCDK2 inhibitor is administered in an amount of from about 0.1 μM toabout 1.0×10⁴ μM. In yet a further aspect, the CDK2 inhibitor isadministered in an amount of from about 1.0 μM to about 1.0×10⁴ μM.

In a further aspect, the CDK2 inhibitor is administered locally. In astill further aspect, the CDK2 inhibitor is administered systemically.

In a further aspect, the CDK2 inhibitor is administered at least onceevery three weeks. In a still further aspect, the CDK2 inhibitor isadministered at least once every week. In yet a further aspect, the CDK2inhibitor is administered at least once every 24 h. In an even furtheraspect, the CDK2 inhibitor is administered at least once every fourhours. In a still further aspect, the CDK2 inhibitor is administered atleast once every one hour.

In a further aspect, the CDK2 inhibitor is administered in an amount offrom about 0.001 μM to about 1.0×10⁴ μM at least once every three weeks.

In a further aspect, the hearing impairment is noise-induced. In a stillfurther aspect, the noise-induced hearing loss is temporary. In yet afurther aspect, the noise-induced hearing loss is permanent.

In a further aspect, the hearing impairment is drug-induced. In a stillfurther aspect, the drug is a chemotherapeutic agent. In yet a furtheraspect, the chemotherapeutic agent is platinum-based. In an even furtheraspect, the platinum-based chemotherapeutic agent is selected fromcarboplatin, cisplatin, transplatin, nedaplatin, oxaliplatin,picoplatin, satraplatin, transplatin, and triplatin, or apharmaceutically acceptable salt thereof. In a still further aspect, theplatinum-based chemotherapeutic agent is cisplatin, or apharmaceutically acceptable salt thereof. In yet a further aspect, thedrug is an antibiotic. In an even further aspect, the antibiotic isselected from daunorubicin, doxorubicin, epirubicin, idarubicin,actinomycin-D, bleomycin, mitomycin-C, amikacin, apramycin, arbekacin,astromicin, bekanamycin, dibekacin, framycetin, gentamicin, hygromycinB, isepamicin, kanamycin, neomycin, netilmicin, paromomycin,rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin,tobramycin, and verdamicin, or a pharmaceutically acceptable saltthereof.

In a further aspect, the hearing impairment is age-related.

In a further aspect, the hearing impairment is related to a balance ororientation-related disorder. Examples of balance disorders include, butare not limited to, induced or spontaneous vertigo, dysequilibrium,increased susceptibility to motion sickness, nausea, vomiting, ataxia,labyrinthitis, oscillopsia, nystagmus, syncope, lightheadedness,dizziness, increased falling, difficulty walking at night, Meniere'sdisease, and difficulty in visual tracking and processing.

In a further aspect, the subject has been diagnosed with a need forprevention of hearing impairment prior to the administering step.

In a further aspect, the method further comprises identifying a subjectat risk for developing a hearing impairment prior to the administeringstep.

G. Methods of Preventing Hearing Impairment

In one aspect, disclosed are methods of preventing hearing impairment,the method comprising administering to a subject a CDK2 inhibitor in anamount of from about 0.001 μM to about 1.0×10⁴ μM at least once everythree weeks, or a pharmaceutically acceptable salt thereof.

In one aspect, disclosed are methods of preventing hearing impairment,the method comprising administering to a subject a compound selectedfrom:

or a pharmaceutically acceptable salt thereof, in an amount of fromabout 0.001 μM to about 1.0×10⁴ μM at least once every three weeks.

In one aspect, disclosed are method of preventing hearing impairment,the method comprising administering to a subject a compound selectedfrom:

or a pharmaceutically acceptable salt thereof, in an amount of fromabout 0.001 μM to about 1.0×10⁴ at least once every three weeks.

Examples of hearing impairment include, but are not limited to, hearingloss, deafness, tinnitus, ringing, Presbyacusis, auditory neuropathy,acoustic trauma, acoustic neuroma, Pendred syndrome, Usher syndrome,Wardenburg syndrome, non-syndromic sensorineural deafness, otitis media,otosclerosis, Meniere's disease, ototoxicity, labyrinthitis, as well ashearing impairments caused by infection (i.e., measles, mumps, ormeningitis), medicines such as antibiotics, and some cancer treatments(i.e., chemotherapy and radiation therapy).

More than one billion teens and young adults worldwide are at risk ofhearing loss from exposure to loud music, as recently reported by theWorld Health Organization(http:/www.cnn.com/2015/03/06/health/hearing-loss-loud-music/index.html).Many other noise exposures, including occupational settings andconsumer-operated devices, also cause NIHL, which is among the mostcommon physical complaints and which detracts significantly from theability to converse, communicate, and participate in everyday life (thusreducing general quality of life of the individual and the family).Acute or chronic acoustic overexposure has put more than 40 million USworkers at risk of permanent hearing loss (Kopke et al., 2007).

Biological protection of hearing is more promising than currentlyavailable mechanical protective devices. Hearing aids are frequentlyproblematic because of their high cost and their many technical issues.Ideally, service men and women could take protective drugs beforeentering high-risk or high-noise settings and would then be protectedfrom noise injury with no effect on performance. To date, there are noFDA-approved drugs for protection against noise- and TBI-associatedhearing loss.

In a further aspect, the CDK2 inhibitor is selected from a paullonederivative, a purine derivative, and a3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceuticallyacceptable salt thereof. In a still further aspect, the CDK2 inhibitoris selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the subject is a mammal. In a still further aspect,the mammal is human.

In a further aspect, the CDK2 inhibitor is administered locally. In astill further aspect, the CDK2 inhibitor is administered systemically.In yet a further aspect, the CDK2 inhibitor is administered locally tothe inner ear of the subject. In an even further aspect, the CDK2inhibitor is administered via injection into one or more of the scalatympani, cochlear duct, scala vestibule of the cochlea, into theauditory nerve trunk in the internal auditory meatus, or into the middleear space across the transtympanic membrane/ear drum.

In a further aspect, the hearing impairment is noise-induced. In a stillfurther aspect, the noise-induced hearing loss is temporary. In yet afurther aspect, the noise-induced hearing loss is permanent.

In a further aspect, the hearing impairment is drug-induced. In a stillfurther aspect, the drug is a chemotherapeutic agent. In yet a furtheraspect, the chemotherapeutic agent is platinum-based. In an even furtheraspect, the platinum-based chemotherapeutic agent is selected fromcarboplatin, cisplatin, transplatin, nedaplatin, oxaliplatin,picoplatin, satraplatin, transplatin, and triplatin, or apharmaceutically acceptable salt thereof. In a still further aspect, theplatinum-based chemotherapeutic agent is cisplatin, or apharmaceutically acceptable salt thereof. In yet a further aspect, thedrug is an antibiotic. In an even further aspect, the antibiotic isselected from daunorubicin, doxorubicin, epirubicin, idarubicin,actinomycin-D, bleomycin, mitomycin-C, amikacin, apramycin, arbekacin,astromicin, bekanamycin, dibekacin, framycetin, gentamicin, hygromycinB, isepamicin, kanamycin, neomycin, netilmicin, paromomycin,rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin,tobramycin, and verdamicin, or a pharmaceutically acceptable saltthereof.

In a further aspect, the hearing impairment is age-related.

In a further aspect, the hearing impairment is related to a balance ororientation-related disorder. Examples of balance disorders include, butare not limited to, induced or spontaneous vertigo, dysequilibrium,increased susceptibility to motion sickness, nausea, vomiting, ataxia,labyrinthitis, oscillopsia, nystagmus, syncope, lightheadedness,dizziness, increased falling, difficulty walking at night, Meniere'sdisease, and difficulty in visual tracking and processing.

H. Methods of Using the Compositions

The compounds and compositions are further useful in methods for theprevention, treatment, control, amelioration, or reduction of risk ofthe hearing impairments and disorders noted herein. The compounds andcompositions are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned hearing impairments and disorders in combination withother agents.

Also provided are methods of using of a disclosed composition ormedicament. In one aspect, the method of use is directed to thetreatment of a disorder. In a further aspect, the disclosed compoundscan be used as single agents or in combination with one or more otherdrugs in the treatment, prevention, control, amelioration, or reductionof risk of the aforementioned diseases, disorders and conditions forwhich the compound or the other drugs have utility, where thecombination of drugs together are safer or more effective than eitherdrug alone. The other drug(s) can be administered by a route and in anamount commonly used therefore, contemporaneously or sequentially with adisclosed compound. When a disclosed compound is used contemporaneouslywith one or more other drugs, a pharmaceutical composition in unitdosage form containing such drugs and the disclosed compound ispreferred. However, the combination therapy can also be administered onoverlapping schedules. It is also envisioned that the combination of oneor more active ingredients and a disclosed compound can be moreefficacious than either as a single agent.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

1. Manufacture of a Medicament

In one aspect, the invention relates to a medicament comprising a CDK2inhibitor, or a pharmaceutically acceptable salt thereof; and one ormore of at least one agent known to treat a hearing impairment, or apharmaceutically acceptable salt thereof, and at least one agent knownto prevent a hearing impairment, or a pharmaceutically acceptable saltthereof.

In various aspects, the invention relates methods for the manufacture ofa medicament for treating and/or preventing hearing impairmentcomprising combining one or more disclosed compounds, products, orcompositions or a pharmaceutically acceptable salt thereof, with apharmaceutically acceptable carrier. It is understood that the disclosedmethods can be performed with the disclosed compounds, products, andpharmaceutical compositions. It is also understood that the disclosedmethods can be employed in connection with the disclosed methods ofusing.

2. Use of Compounds and Compositions

Also provided are the uses of the disclosed compounds and compositions.

Thus, in one aspect, the invention relates to the uses of a CDK2inhibitor, or a pharmaceutically acceptable salt thereof; and one ormore of at least one agent known to treat a hearing impairment, or apharmaceutically acceptable salt thereof, and at least one agent knownto prevent a hearing impairment, or a pharmaceutically acceptable saltthereof.

In a further aspect, the invention relates to the use of a CDK2inhibitor, or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of a hearing impairment ordisorder.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, andone or more of at least one agent known to treat a hearing impairment,or a pharmaceutically acceptable salt thereof, and at least one agentknown to prevent a hearing impairment, or a pharmaceutically acceptablesalt thereof, for use as a medicament.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, andone or more of at least one agent known to treat a hearing impairment,or a pharmaceutically acceptable salt thereof, and at least one agentknown to prevent a hearing impairment, or a pharmaceutically acceptablesalt thereof, wherein a pharmaceutically acceptable carrier isintimately mixed with a therapeutically effective amount of the CDK2inhibitor, the at least one agent known to treat a hearing impairment,or the at least one agent known to prevent a hearing impairment.

In various aspects, the use relates to the treatment of a hearingimpairment or disorder in a vertebrate animal. In a further aspect, theuse relates to the treatment of a hearing impairment or disorder in ahuman subject.

In a further aspect, the use is the treatment of a hearing impairment ordisorder. In a still further aspect, the use is the treatment of ahearing impairment. In yet a further aspect, the use is the treatment ofa hearing disorder.

It is understood that the disclosed uses can be employed in connectionwith the disclosed compounds, methods, compositions, and kits. In afurther aspect, the invention relates to the use of a disclosed compoundor composition of a medicament for the treatment of a hearing impairmentor disorder in a mammal.

In a further aspect, the invention relates to the use of a disclosedcompound or composition in the manufacture of a medicament for thetreatment of a hearing impairment or disorder selected from hearingloss, deafness, tinnitus, ringing, Presbyacusis, auditory neuropathy,acoustic trauma, acoustic neuroma, Pendred syndrome, Usher syndrome,Wardenburg syndrome, non-syndromic sensorineural deafness, otitis media,otosclerosis, Meniere's disease, ototoxicity, labyrinthitis, as well ashearing impairments caused by infection (i.e., measles, mumps, ormeningitis), medicines such as antibiotics, and some cancer treatments(i.e., chemotherapy and radiation therapy).

In a further aspect, the invention relates to the use of a disclosedcompound or composition in the manufacture of a medicament for thetreatment of a hearing impairment or disorder.

In a further aspect, the invention relates to the use of a disclosedcompound or composition in the treatment of hair cell loss and anydisorder that arises as a consequence of cell loss in the ear, such ashearing impairments (e.g., because of trauma or prolonged exposure toloud noises), deafness (e.g., because of a genetic or congenitaldefect), and vestibular disorders (e.g., including bilateral andunilateral vestibular dysfunction), for example, by promotingdifferentiation (e.g., complete or partial differentiation) of one ormore cells into one or more cells capable of functioning as sensorycells of the ear, e.g., hair cells. Subjects benefiting from suchtreatment include those at risk of hair cell loss and/or a patient withhair cell loss. For example, a subject having or at risk for developinga hearing loss can hear less well than the average subject (e.g., anaverage human being), or less well than a subject before experiencingthe hearing loss. For example, hearing can be diminished by at least 5%,10%, 30%, 50% or more.

In various aspects, the methods described herein can be used to generatehair cell growth in the ear and/or to increase the number of hair cellsin the ear (e.g., in the inner, middle, and/or outer ear). In thisrespect, an effective amount of a stimulatory agent and an inhibitoryagent described herein is an amount that increases the number of haircells in the ear by about 2-, 3-, 4-, 6-, 8-, or 10-fold, or more, ascompared to the number of hair cells before treatment. This new haircell growth can effectively restore or establish at least a partialimprovement in the subject's ability to hear. For example,administration of a stimulatory agent and an inhibitory agent of thisinvention can improve hearing loss by about 5, 10, 15, 20, 40, 60, 80,100% or more.

In various aspects, the agents and methods described herein can be usedprophylactically, such as to prevent, reduce, or delay progression ofhearing loss, deafness, or other auditory disorders associated with lossof inner ear function.

3. Kits

In one aspect, disclosed are kits comprising a CDK2 inhibitor, or apharmaceutically acceptable salt thereof; and one or more of: (a) atleast one agent known to treat a hearing impairment; (b) at least oneagent known to prevent a hearing impairment; (c) at least one antibioticagent; (d) at least one chemotherapeutic agent; (e) instructions fortreating a hearing impairment; and (f) instructions for preventing ahearing impairment.

In one aspect, disclosed are kits comprising a compound selected from:

or a pharmaceutically acceptable salt thereof; and one or more of: atleast one agent known to treat a hearing impairment; at least one agentknown to prevent a hearing impairment; at least one antibiotic agent; atleast one chemotherapeutic agent; instructions for treating a hearingimpairment; and instructions for preventing a hearing impairment.

In one aspect, disclosed are kits comprising a compound selected from:

or a pharmaceutically acceptable salt thereof; and one or more of: (a)at least one agent known to treat a hearing impairment; (b) at least oneagent known to prevent a hearing impairment; (c) at least one antibioticagent; (d) at least one chemotherapeutic agent; (e) instructions fortreating a hearing impairment; and (f) instructions for preventing ahearing impairment.

In various aspects, the agents and pharmaceutical compositions describedherein can be provided in a kit. The kit can also include combinationsof the agents and pharmaceutical compositions described herein.

In various aspects, the informational material can be descriptive,instructional, marketing or other material that relates to the methodsdescribed herein and/or to the use of the agents for the methodsdescribed herein. For example, the informational material may relate tothe use of the agents herein to treat a subject who has, or who is atrisk for developing, a hearing impairment. The kits can also includeparaphernalia for administering the agents of this invention to a cell(in culture or in vivo) and/or for administering a cell to a patient.

In various aspects, the informational material can include instructionsfor administering the pharmaceutical composition and/or cell(s) in asuitable manner to treat a human, e.g., in a suitable dose, dosage form,or mode of administration (e.g., a dose, dosage form, or mode ofadministration described herein). In a further aspect, the informationalmaterial can include instructions to administer the pharmaceuticalcomposition to a suitable subject, e.g., a human having, or at risk fordeveloping, a hearing impairment.

In various aspects, the composition of the kit can include otheringredients, such as a solvent or buffer, a stabilizer, a preservative,a fragrance or other cosmetic ingredient. In such aspects, the kit caninclude instructions for admixing the agent and the other ingredients,or for using one or more compounds together with the other ingredients.

In a further aspect, the CDK2 inhibitor and the at least one agent knownto treat a hearing impairment are co-formulated. In a still furtheraspect, the CDK2 inhibitor and the at least one agent known to treat ahearing impairment are co-packaged.

In a further aspect, the agent known to treat a hearing impairment isselected from an antiepileptic drug blocking T-type calcium channels; ananticonvulsant; a synthetic glucocorticoid; a loop diuretic; ananti-oxidant; a proton pump inhibitor; a PDE5 inhibitor; and a mGluR7inhibitor. In a still further aspect, the agent known to treat a hearingimpairment is selected from trimethadione; mibefrabil; ethosuximide;3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide(TTA-P2); NNC 55-0396; ML 218; nilvadipine; valproic acid;oxcarbazepine; phenobarbital; phenytoin; zonisamide; nicardipine;chlordiazepoxide; sipatrigine; halothane; octanol; pimozide;penfluridol; fluspirilene; thioridazine; clozapine; haloperidol;tetramethrin; tetrandrine; amiodarone; bepridil; cinnarizine;flunarizine; amiloride; anandamide; dexamethasone; methylprednisolone;N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide;2-phenyl-1,2-benzisoselenazol-3-one (ebselen); sodium thiosulfate;D-methionine; furosemide; N-acetyl-L-cysteine; vitaminsA; vitamin C;vitamin E; vigabatrin; omeprazole; lansoprazole; pantoprazole;rabeprazole; esomerprazole; pariprazole; leminoprazole;3,3′-diindolylmethane; vardenafil; sildenafil; tadalafil; udenafil;dasantafil; avanafil; SLx2101; LAS34179;N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride;R(+)-N-propargyl-1-aminoindan; and L-camitine.

In a further aspect, the CDK2 inhibitor and the at least one agent knownto prevent a hearing impairment are co-formulated. In a still furtheraspect, the CDK2 inhibitor and the at least one agent known to prevent ahearing impairment are co-packaged.

In a further aspect, the CDK2 inhibitor and the at least one antibioticagent are co-formulated. In a still further aspect, the CDK2 inhibitorand the at least one antibiotic agent are co-packaged.

In a further aspect, the CDK2 inhibitor and the at least onechemotherapeutic agent are co-formulated. In a still further aspect, theCDK2 inhibitor and the at least one chemotherapeutic agent areco-packaged.

In a further aspect, the chemotherapeutic agent is a platinum-basedagent. In a still further aspect, the platinum-based agent is selectedfrom carboplatin, cisplatin, transplatin, nedaplatin, oxaliplatin,picoplatin, satraplatin, transplatin, and triplatin. In yet a furtheraspect, the platinum-based agent is cisplatin.

In a further aspect, the kit further comprises a plurality of dosageforms, the plurality comprising one or more doses; wherein each dosecomprises an effective amount of a CDK2 inhibitor and the at least oneagent known to treat a hearing impairment. In a still further aspect,the effective amount is a therapeutically effective amount. In yet afurther aspect, the effective amount is a prophylactically effectiveamount. In an even further aspect, each dose of the CDK2 inhibitor andthe agent known to treat a hearing impairment are co-packaged. In astill further aspect, each dose of the CDK2 inhibitor and the agentknown to treat a hearing impairment are co-formulated.

In a further aspect, the kit further comprises a plurality of dosageforms, the plurality comprising one or more doses; wherein each dosecomprises an effective amount of a CDK2 inhibitor and the at least oneagent known to prevent a hearing impairment. In a still further aspect,the effective amount is a therapeutically effective amount. In yet afurther aspect, the effective amount is a prophylactically effectiveamount. In an even further aspect, each dose of the CDK2 inhibitor andthe agent known to prevent a hearing impairment are co-packaged. In astill further aspect, each dose of the CDK2 inhibitor and the agentknown to prevent a hearing impairment are co-formulated.

In a further aspect, the kit further comprises a plurality of dosageforms, the plurality comprising one or more doses; wherein each dosecomprises an effective amount of a CDK2 inhibitor and the at least oneantibiotic agent. In a still further aspect, the effective amount is atherapeutically effective amount. In yet a further aspect, the effectiveamount is a prophylactically effective amount. In an even furtheraspect, each dose of the CDK2 inhibitor and the antibiotic agent areco-packaged. In a still further aspect, each dose of the CDK2 inhibitorand the antibiotic agent are co-formulated.

In a further aspect, the kit further comprises a plurality of dosageforms, the plurality comprising one or more doses; wherein each dosecomprises an effective amount of a CDK2 inhibitor and the at least onechemotherapeutic agent. In a still further aspect, the effective amountis a therapeutically effective amount. In yet a further aspect, theeffective amount is a prophylactically effective amount. In an evenfurther aspect, each dose of the CDK2 inhibitor and the chemotherapeuticagent are co-packaged. In a still further aspect, each dose of the CDK2inhibitor and the chemotherapeutic agent are co-formulated.

In a further aspect, the dosage forms are formulated for topicaladministration. In a still further aspect, the dosage forms areformulated for injection into the luminae of the cochlea, the auditorynerve trunk in the internal auditory meatus, the scala tympani, or themiddle ear space across the transtympanic membrane/ear drum; or, ifpresent, into a cochlear implant.

In a further aspect, the CDK2 inhibitor is formulated for topicaladministration; and the agent known to treat a hearing impairment isformulated for injection into the luminae of the cochlea, the auditorynerve trunk in the internal auditory meatus, the scala tympani, or themiddle ear space across the transtympanic membrane/ear drum; or, ifpresent, into a cochlear implant. In a still further aspect, the CDK2inhibitor is formulated for injection into the luminae of the cochlea,the auditory nerve trunk in the internal auditory meatus, the scalatympani, or the middle ear space across the transtympanic membrane/eardrum; or, if present, into a cochlear implant; and the agent known totreat a hearing impairment is formulated for topical administration.

In a further aspect, the CDK2 inhibitor is formulated for topicaladministration; and the agent known to prevent a hearing impairment isformulated for injection into the luminae of the cochlea, the auditorynerve trunk in the internal auditory meatus, the scala tympani, or themiddle ear space across the transtympanic membrane/ear drum; or, ifpresent, into a cochlear implant. In a still further aspect, the CDK2inhibitor is formulated for injection into the luminae of the cochlea,the auditory nerve trunk in the internal auditory meatus, the scalatympani, or the middle ear space across the transtympanic membrane/eardrum; or, if present, into a cochlear implant; and the agent known toprevent a hearing impairment is formulated for topical administration.

In a further aspect, the CDK2 inhibitor is formulated for intravenousadministration and the chemotherapeutic agent is formulated for oraladministration. In a still further aspect, the CDK2 inhibitor isformulated for oral administration and the chemotherapeutic agent isformulated for intravenous administration. In yet a further aspect, theCDK2 inhibitor is formulated for intravenous administration and theantibiotic agent is formulated for oral administration. In an evenfurther aspect, the CDK2 inhibitor is formulated for oral administrationand the antibiotic agent is formulated for intravenous administration.

4. Subjects

In various aspects, the subject of the herein disclosed methods is avertebrate, e.g., a mammal. Thus, the subject of the herein disclosedmethods can be a human, non-human primate, horse, pig, rabbit, dog,sheep, goat, cow, cat, guinea pig or rodent. The term does not denote aparticular age or sex. Thus, adult and newborn subjects, as well asfetuses, whether male or female, are intended to be covered. A patientrefers to a subject afflicted with a disease or disorder. The term“patient” includes human and veterinary subjects.

In some aspects of the disclosed methods, the subject has been diagnosedwith a need for treatment prior to the administering step. In someaspects of the disclosed method, the subject has been diagnosed with ahearing impairment or disorder prior to the administering step. In someaspects of the disclosed methods, the subject has been identified with aneed for treatment prior to the administering step. In one aspect, asubject can be treated prophylactically with a compound or compositiondisclosed herein, as discussed herein elsewhere.

a. Dosage

Toxicity and therapeutic efficacy of the agents and pharmaceuticalcompositions described herein can be determined by standardpharmaceutical procedures, using either cells in culture or experimentalanimals to determine the LD₅₀ (the dose lethal to 50% of the population)and the ED₅₀ (the dose therapeutically effective in 50% of thepopulation). The dose ratio between toxic and therapeutic effects is thetherapeutic index and can be expressed as the ratio LD₅₀/ED₅₀.Polypeptides or other compounds that exhibit large therapeutic indicesare preferred.

Data obtained from cell culture assays and further animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity, andwith little or no adverse effect on a human's ability to hear. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any agents usedin the methods described herein, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose can beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (that is, the concentrationof the test compound which achieves a half-maximal inhibition ofsymptoms) as determined in cell culture. Such information can be used tomore accurately determine useful doses in humans. Exemplary dosageamounts of a differentiation agent are at least from about 0.01 to 3000mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1,2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day,or more.

The formulations and routes of administration can be tailored to thedisease or disorder being treated, and for the specific human beingtreated. For example, a subject can receive a dose of the agent once ortwice or more daily for one week, one month, six months, one year, ormore. The treatment can continue indefinitely, such as throughout thelifetime of the human. Treatment can be administered at regular orirregular intervals (once every other day or twice per week), and thedosage and timing of the administration can be adjusted throughout thecourse of the treatment. The dosage can remain constant over the courseof the treatment regimen, or it can be decreased or increased over thecourse of the treatment.

In various aspects, the dosage facilitates an intended purpose for bothprophylaxis and treatment without undesirable side effects, such astoxicity, irritation or allergic response. Although individual needs mayvary, the determination of optimal ranges for effective amounts offormulations is within the skill of the art. Human doses can readily beextrapolated from animal studies (Katocs et al., (1990) Chapter 27 inRemington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., MackPublishing Co., Easton, Pa.). In general, the dosage required to providean effective amount of a formulation, which can be adjusted by oneskilled in the art, will vary depending on several factors, includingthe age, health, physical condition, weight, type and extent of thedisease or disorder of the recipient, frequency of treatment, the natureof concurrent therapy, if required, and the nature and scope of thedesired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman'sThe Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al.,eds., McGraw-Hill, New York, N.Y.).

b. Routes of Administration

Also provided are routes of administering the disclosed compounds andcompositions. The compounds and compositions of the present inventioncan be administered by direct therapy using systemic administrationand/or local administration. In various aspects, the route ofadministration can be determined by a patient's health care provider orclinician, for example following an evaluation of the patient. Invarious aspects, an individual patient's therapy may be customized,e.g., the type of agent used, the routes of administration, and thefrequency of administration can be personalized. Alternatively, therapymay be performed using a standard course of treatment, e.g., usingpre-selected agents and pre-selected routes of administration andfrequency of administration.

Systemic routes of administration can include, but are not limited to,parenteral routes of administration, e.g., intravenous injection,intramuscular injection, and intraperitoneal injection; enteral routesof administration e.g., administration by the oral route, lozenges,compressed tablets, pills, tablets, capsules, drops (e.g., ear drops),syrups, suspensions and emulsions; rectal administration, e.g., a rectalsuppository or enema; a vaginal suppository; a urethral suppository;transdermal routes of administration; and inhalation (e.g., nasalsprays).

In various aspects, the compounds and compositions described herein canbe administered to a patient, e.g., a patient identified as being inneed of treatment for hair cell loss, using a local route ofadministration. Such local routes of administration includeadministering the agents described herein into the ear of a patientand/or the inner ear of a patient, for example, by injection and/orusing a pump or placing a gelfoam for constant release of compounds intothe inner ear.

In various aspects, a pharmaceutical composition can be injected intothe ear (e.g., auricular administration), such as into the luminae ofthe cochlea (e.g., the Scala media, Sc vestibulae, and Sc tympani),e.g., using a syringe, e.g., a single-dose syringe. For example, thecompounds and compositions described herein can be administered byintratympanic injection (e.g., into the middle ear), and/or injectionsinto the outer, middle, and/or inner ear. Such methods are routinelyused in the art, for example, for the administration of steroids andantibiotics into human ears. Injection can be, for example, through theround window of the ear or through the cochlear capsule. Other inner earadministration methods are known in the art (see, e.g., Salt andPlontke, Drug Discovery Today 2005, 10, 1299).

In various aspects, the pharmaceutical composition can be administeredin situ, via a catheter or pump. A catheter or pump can, for example,direct a pharmaceutical composition into the cochlear luminae or theround window of the ear and/or the lumen of the colon. Exemplary drugdelivery apparatus and methods suitable for administering one or more ofthe compounds described herein into an ear, e.g., a human ear, aredescribed in US 2006/0030837 and U.S. Pat. No. 7,206,639. In a furtheraspect, a catheter or pump can be positioned, e.g, in the ear (e.g., theouter, middle, and/or inner ear) of a patient during a surgicalprocedure. In a still further aspect, a catheter or pump can bepositioned, e.g., in the ear (e.g., the outer, middle, and/or inner ear)of a patient without the need for a surgical procedure.

In various aspects, one or more of the compounds and compositionsdescribed herein can be administered in combination with a mechanicaldevice such as a cochlear implant or a hearing aid, which is worn in theouter ear. An exemplary cochlear implant that is suitable for use withthe present invention is described in US 2007/0093878.

In various aspects, the modes of administration described above may becombined in any order.

In various aspects, the compounds and compositions described herein canbe administered via cell therapy, wherein cells are contacted ex vivowith the combination of agents described herein to promote complete orpartial differentiation of the cells to or toward a mature cell type ofthe inner ear (e.g., a hair cell) in vitro. Cells resulting from suchmethods can then be transplanted or implanted into a patient in need ofsuch treatment.

In various aspects, suitable cells can be derived from a mammal, such asa human, mouse, rat, pig, sheep, goat, or non-human primate. Forexample, stem cells have been identified and isolated from the mouseutricular macula (Li, H., et al. (2003) Nature Medicine 9, 1293-1299).The cells can also be obtained from a patient to whom they willsubsequently be re-administered.

In various aspects, suitable cells (e.g., a stem cell, progenitor cell,and/or support cell) may be isolated from the inner ear of an animal.Specifically, suitable cells can be obtained from the cochlear organ ofCorti, the modiolus (center) of the cochlea, the spiral ganglion of thecochlea, the vestibular sensory epithelia of the saccular macula, theutricular macula, or the cristae of the semicircular canals. The stemcell, progenitor cell, and/or supporting cells can also be obtained,however, from other tissues such as bone marrow, blood, skin, or an eye.The cells employed can be obtained from a single source (e.g, the ear ora structure or tissue within the ear) or a combination of sources (e.g.,the ear and one or more peripheral tissues (e.g., bone marrow, blood,skin, or an eye).

I. Examples

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. Primary Screen of a Bioactive Library for Reduction ofCisplatin-Induced Apoptosis in the HEI-OC1 Cell Line

Caspase-3 activation is an important downstream molecular event known tooccur in the majority of cellular pathways leading to apoptosis,including apoptosis of inner ear cells. Previous work has shown thatinhibition of caspases, for example, by zVAD-fmk, an irreversiblegeneral caspase inhibitor, confers robust protection againstcisplatin-induced cell death (Liu et al. (1998) Neuroreport 9:2609-2614). For this screen, caspase-3 cleavage was chosen as theendpoint indicating cisplatin-induced cell death, as it allowed theinhibition of cell death to be monitored at the level of anyintracellular molecular target upstream of caspase-3 cleavage in thecell line. Pifithrin-α was also chosen as a reference compound for thescreen, as it provided good protection against cisplatin ototoxicity byinhibiting caspase-3 cleavage with an IC₅₀ of 17 μM. Pifithrin—a, asmall molecule that inhibits p53, was shown to suppress the expressionof p53, caspase-3, and caspase-1 in mouse cochlear explants (Zhang etal. (2003) Neuroscience 120: 191-205). Pifithrin-α has previously beenshown to confer reasonable protection from cisplatin-induced cell deathin cell lines and, importantly, in mouse cochlear explants atconcentrations of 20-100 μM (Zhang et al. (2003) Neuroscience 120:191-205), although at these doses it was reported to damage the haircell stereocillia.

To measure cell death induced by cisplatin in cochlear hair cells, theHEI-OC1 immortalized inner ear cell line isolated originally from P7organs of Corti of the Immortomouse (Kalinec et al. (2003) Adiol.Neurootol. 8: 177-189) was used. This cell line has been shown to serveas a good model of inner ear cells (Kim et al. (2010) J. Neurosci. 30:3933-3946), and it was independently confirmed by qRT-PCR that the cellsused in this screen express the hair cell markers Myo6 and Myo7a.

This screen is also described in Teitz, T., Goktug, A. N., Chen, T.,Zuo, J., 2016. Development of cell-based high throughput chemicalscreens for protection against cisplatin-induced ototoxicity In:Sokolowski, B., (Ed.), Auditory and Vestibular Research, Methods andProtocols, Second Edition. Humana Press. pp 419-430. doi:10.1007/978-1-4939-3615-1_22.

Before starting the automated high-throughput screen (HTS) accomplishedwith the help of robots in 384-well plates, assay conditions wereoptimized on the bench, including the cell number plated (1600 cells perwell), cisplatin concentration (50 μM, based on the dose-responsecurve), incubation time (22 hrs at 33° C., 10% CO₂), and concentrationof the reference compound, pifithrin-α. The Promega Caspase-3/7 Gloassay, which allows measurement of light emitted as the result ofcaspase cleavage and is suitable for HTS, was used. The linearity of theCaspase-3/7 Glo assay was validated and it was verified that 0.5% DMSOhad no effect on cell death kinetics. The Caspase-3/7 Glo assay was thentested for reproducibility on the St. Jude robot systems. By using apintool, test compounds were added to the screen to a finalconcentration of 8 μM, and cisplatin solution was added immediately toeach well to a final concentration of 50 μM. Cells were incubated withthe test compounds and cisplatin for 22 hrs at 33° C., 10% CO₂ with themedium as previously described (Kalinec et al. (2003) Adiol. Neurootol.8: 177-189); no γ-interferon was added. The 384-well plates were shakenand spun after compound addition to enhance assay reproducibility.

The assay positive control, pifithrin-α, induced 50% reduction ofcaspase-3/7 activity at 17 μM (IC₅₀) and full reduction at 34 μM.Pifithrin-α was added to each of the 34 plates as a screening qualitycontrol. FIG. 1 shows the percent activity of caspase-3/7 in screeningof the 4,359 unique bioactive compounds, including >844 FDA approveddrugs. Cisplatin-induced caspase-3/7 activity was reduced by 60% or moreby 177 compounds, which were further analyzed for dose response andtoxicity.

Referring to FIG. 1, a screen of a bioactive compound library, including4,359 unique compounds and 844 FDA-approved drugs, was conducted. Thecell-based screen average z′ was 0.75, signal window was 12, and signalfold was 4.9. Cells treated with 50 μM cisplatin were assigned 100%caspase-3/7 activity. Cells not treated with cisplatin (grown in mediaonly) were assigned 0% caspase-3/7 activity. 177 compounds were found todecrease cisplatin-induced caspase-3/7 activity by 60% or more (seeblack line and below).

2. Dose-Response and Toxicity of the Top Hits from the Primary Screen

The Caspase-3/7 Glo assay was used as described above to test the 177top hit compounds for protection against cisplatin-induced cell death.Ten serial 1:3 dilutions (40 μM to 40 nM) of each compound were testedin triplicate in the presence of 50 μM cisplatin. To measure theviability of the HEI-OC1 cells treated with these compounds alone, thecompounds were added to the cells without cisplatin at the same finalconcentrations of 40 μM to 40 nM. Cell viability was assayed intriplicate by using the Promega Cell Titer Glo assay (CTG), whichquantifies the ATP released from live cells and is suitable for HTS.Cells grown in media only, without compounds, under identical conditionsserved as positive control for 100% viability. Cells treated with a 100%lethal concentration of staurosporine for 22 hours were controls for 0%viability. The results of the caspase-3/7 assay and the CTG viabilityassay are shown for three known compounds (pifithrin-α, zVAD-fmk, andEbselen, shown in Teitz et al., 2016, Auditory and Vestibular Research,Methods and Protocols, Second Edition. Humana Press. pp 419-430) andfive representative compounds (3, 4, 1, 12, and 9) in FIG. 2a-e . Eachplate contained wells for the reference compound pifithrin-α. One of thetop hits was zVAD-fmk, an irreversible, potent general caspase inhibitorpredicted to appear in this screen. zVAD-fmk has been shown to inhibitcisplatin-induced cell death in the mouse cochlea with high potency(IC₅₀=0.2 μM) (Atar and Avraham (2010) Neuroscience 168: 851-857; Liu etal. (1998) Neuroreport 9: 2609-2614). However, this compound is unlikelyto be the best choice for therapeutic use in vivo. Another interestinghit from the screen was Ebselen, which is currently being tested forprotection against noise-induced hearing loss in a clinical Phase 2trial (www.soundpharmaceuticals.com). Ebselen showed low potency inprotection against cisplatin and was toxic at the concentration thatinhibited caspase-3/7.

Referring to FIG. 2a-e , dose response curves were generated after 22 hrculture in HEI-OC1 cells. Shown are Caspase-3/7 Glo assay(cisplatin-induced cell death; compound+cisplatin) and Cell Titer Glo(CTG) assay (cell viability; compound only) data for compounds 4, 9, 12,3, and 1 (FIG. 2a-e , respectively). The Caspase-3/7 IC₅₀ activity isindicated for each compound.

Table 1 lists the top 18 compound hits in the screen in terms of highpotency and low toxicity. Their drug status for other diseases andcorresponding mechanism of action are listed in Table 2. The top tencompounds were further evaluated by a viability assay (Cell Titer Glo,Promega) in medulloblastoma neurosphere cell lines and neuroblastomacell lines to test whether they inhibit the ability of cisplatin to killthe tumor cells. The majority had no antagonistic effect on cisplatin'santitumor activity (data not shown) and are therefore safe to usesystemically together with cisplatin during chemotherapy to protectagainst cisplatin-induced hearing loss.

TABLE 1 Cmpd. HEI-OC1 HEI-OC1 No. Cmpd. Name Chemical Structure IC₅₀(μM) LD₅₀ (μM) 1 Leflunomide

3.0 >40 2 Olsalazine sodium

6.2 >40 3 Pelitinib

0.6 >40 4 Kenpaullone

2.1 >40 5 Antimycin A

0.04 >10 6 Cyanocobalamin (vitamin B12)

4.2 >40 7 EHT1864

2.0 >20 8 Lanatoside C

7.6 >40 9 Olomoucine II

0.8 >40 10 2-Mercapto- benzothiazole

7.0 >10 11 Patulin

0.7 >10 12 CDK2 inhibitor II

0.5 >40 13 D-Ribofuranosyl- benzimidazole

4.0 >40 14 GSK JS 84326047A1

1.3 >10 15 Roche (R002830409001)

0.1 >10 16 GSK (AN100368079A1)

0.8 >40 17 GSK (U18675/6/1)

2.1 >40 18 GSK (U11667/23/1)

3.4 >40

TABLE 2 Cmpd. Drug Status For No. Other Diseases Mechanism of Action inOther Diseases 1 FDA approved for Prodrug: pyrimidine synthesisinhibitor for the treatment of rheumatoid arthritis, inhibitor of JNK,active rheumatoid inhibitor of TNF-dependent NF-kB activation, arthritisinhibitor of Cox-2, inhibitor of tyrosine kinase phosphorylation,inhibitor of DHODH (de novo pyrimidine synthesis). 2 FDA approvedDerivative of salicylate: 5-aminosalicyclic acid prodrug used ininflammatory bowel disease, ulcerative colitis, anti-inflammatory andanti- apoptotic regulation. 3 IND phase Irreversible inhibitor ofepidermal growth factor receptor. 4 In vivo, Rodent Inhibitor ofCDK1/cyclin B (IC₅₀ = 400 nM), CDK2/cyclin A (IC₅₀ = 680 nM), CDK5/p25(IC₅₀ = 850 nM), GSK-3β (IC₅₀ = 230 nM), and HCK (MAP4K4) kinases(reduction of HGK- Tak1-Mkk4-JNK-c-Jun cell death signaling cascade) 5In vivo, Antibiotic, inhibitor of mitochondrial electron Rodenttransport and inducer of apoptosis, toxin 6 FDA approved General methylmetabolism, methyl donor for L- methionine synthesis 7 In vivo, RodentInhibitor of Rat family of GTPases and blocks activation by directbinding to Rac1, Rac1b, Rac2, and Rac3 8 IND Phase Cardiac glycoside,inhibitor of Na⁺/K⁺-ATPase 9 In vitro Inhibitor of CDKs 2,5, 7, and 9;inhibitor and substrate of ABCB1 and ABCG2 transporters 10 In vivo,Toxin, multiple mechanisms Rodent 11 In vivo, Rodent Mycotoxin,antibiotic 12 In vitro ATP-competitive, selective inhibitor of CDK2(IC₅₀ = 60 nM) 13 In vitro Inhibitor of CDKs 7 and 9, RNA synthesis 14 —Potent and selective CNS penetrant furan- based inhibitor of B-Rafkinase 15 — Potent oxindole inhibitor of CDK2 16 — Potent and selectiveinhibitor of GSK3 17 — Heterocyclic inhibitor of GSK3 18 —Oxindole-based inhibitor of CDK2

3. Protection Against Cisplatin-Induced Hair Cell Loss in CochlearExplants

The top 13 compounds were texted ex vivo in neonatal (P3) mouse cochlearexplants. P3 wild-type mouse cochleae were dissected and cultured withthe aid of matrigel as previously described (Driver and Kelley (2010)Curr. Protoc. Neurosci. Chapter 4, Unit 4 34: 31-10). After one day ofculture, cisplatin (50 μM) with or without compounds were added togrowth media and incubated for 24 hrs at 37° C. 50 μM cisplatin waschosen because the explant assay consistently showed death at ˜40% ofouter hair cells (OHCs) in the mouse cochlea at this concentration after24 hrs co-incubation (FIG. 3A-G). It is known that OHCs are the firstcells to be damaged ex vivo and in vivo by cisplatin and noise, whileinner hair cells (IHCs) are injured at higher concentrations ofcisplatin or higher levels of noise (Oishi and Schacht (2011) ExpertOpin. Emerg. Drugs 16: 235-245; Zhang et al. (2003) Neuroscience 120:191-205). Cochleae were fixed with 4% paraformaldehyde (PFA) and stainedagainst actin with Phalloidin-Alexa Fluor 568 to determine hair cells'viability, which was also assayed by 4′,6-diamidino-2-phenylindole(DAPI) staining, FM1-43 dye uptake, and immunohistochemistry with knownhair cell markers (Parvalbumin and Myo7a). Cochleae were imaged byconfocal microscopy, two 160 μm regions from middle turns werephotographed, and the number of intact hair cells was counted. Three totwelve cochleae were tested under each condition.

Referring to FIG. 3A-D, compound 4 protects against cisplatin-inducedhair cell loss in mouse cochlear explants. Confocal images of wholemount cochlear explants that have been treated with media (FIG. 3A),cisplatin (FIG. 3B), compound 4 (FIG. 3C), or cisplatin and compound 4(FIG. 3C) for 24 hrs are shown. Phalloidin labels the hair cells.

Referring to FIG. 3E-G, outer hair cell survival (%) when treated withvarious doses (μM) of compounds 4 (FIG. 3E), 9 (FIG. 3F), or 12 (FIG.3G), and/or cisplatin (CIS) are shown. The number of cochlear explantsanalyzed is indicated in each bar. ***P<0.001 using one-way ANOVA testfollowed by Bonferroni comparison.

Ten of these compounds protected the cochlear explants at >2concentrations, as measured by hair cell viability after 24 hr cisplatinco-treatment. Four compounds (1, 4, 9, and 12) showed excellentprotection (100% OHC survival), with IC₅₀ values of 0.1 to 25 μM (FIG. 3shows compound 4; Table 3). The remaining compounds (2, 3, 5-7, and 13)protected 31-76% of the OHCs against cisplatin (Table 3).

TABLE 3 Cmpd. Mouse Explant Mouse Explant No. IC₅₀ (μM) LD₅₀ (μM) 1~25 >50 2 ~30 >30 (For 50%) 3 ~6 <13 (For 50%) 4 ~0.15 >30 5 ~1.8  <4(For 31%) 6 ~21 >21 (For 53%) 7 ~10 <20 (For 58%) 8 >12-76 9 ~2.0 >3310 >49 11 >3-9 12 ~2.0 >12 ~8.0 13 (For 76%)

4. Protection Against Cisplatin-Induced Hair Cell Loss in ZebrafishLateral Lines In Vivo

The top ten compounds as determined by the mouse cochlear explants werefurther tested in the lateral line neuromasts of 5-dayspost-fertilization (dpf) zebrafish larvae in vivo. Hair cells in thezebrafish lateral line are considered homologous to sensory hair cellsin the mammalian inner ear and have similar responses to ototoxic drugs(Ou et al. (2007) Hear. Res. 233: 46-53). Zebrafish are well establishedin vivo system to test cisplatin damage, as the hair cells are easilyaccessible to drugs (Coffin et al. (2013) Apoptosis 18: 393-408; Vlasitset al. (2012) Hear. Res. 294: 153-165). The experiments were performedwith 5-dpf larval zebrafish of the *AB wild-type strain. Dose-responsestudies were performed to find the cisplatin concentration at which mostof the hair cells in each neuromast were killed in the absence of aprotective compound and at the same DMSO concentration (<0.2%). It wasdetermined that 5 μM cisplatin killed 91% of the hair cells withoutaddition of protective compounds in zebrafish treated for 20 hrs (FIG.4A-E, see the data point of 9% survival with “5.0 CIS”). Next, thecisplatin protection effect of the top ten compounds as determined bythe experiments herein above was tested. As positive controls in theseexperiments, Paroxetine and Benzamil were used at concentrationspreviously shown to confer cisplatin protection in zebrafish (Vlasits etal. (2012) Hear. Res. 294: 153-165; FIG. 4A-E).

Referring to FIG. 4A-D, compound 4 protects against cisplatin-inducedhair cell loss in zebrafish lateral lines in vivo. Lateral lineneuromasts (white dots) in the zebrafish head were visualized bystaining with 0.005% DASPEI vital dye after treatment with medium (FIG.4A), cisplatin (FIG. 4B), compound 4 and Benzamil (FIG. 4C), or compound4 and cisplatin (FIG. 4D). Benzamil and Paroxetine are compounds knownto protect against cisplatin-induced hair cell loss in zebrafish(Vlasits et al. (2012) Hear. Res. 294: 153-165).

Referring to FIG. 4E, hair cell survival (%) at various doses (μM) ofcompound 4 and cisplatin are shown. The number of zebrafish tested ineach condition was 3-13. Standard errors are shown for each condition.***P<0.001 using one-way ANOVA followed by Bonferroni comparison. ND:not detected.

Experiments were performed in 24-well plates with 5 fish per well involumes of 1-2 mL. Fish were incubated with 5 μM and stained with 0.005%DASPEI vital dye for 15 minutes. After two washes with egg water, fishwere visualized in an epiflourescence microscope. Ten specificneuromasts in each fish were scored based on their intensity, in a scalefrom 0 (no labeling) to 2 (high intensity), as described previously(Owens et al. (2009) Hear. Res. 253: 32-41). Results were plotted aspercent survival of hair cells in the cisplatin-treated fish relative tothe untreated fish (FIG. 4A-E).

Of the ten compounds tested, only compound 4 showed significantprotection of zebrafish neuromasts against cisplatin-induced hair cellloss (FIG. 4A-E; Table 4). Without wishing to be bound by theory, theseresults suggest that most of these compounds protect through molecularmechanisms that are specific and unique to mammalian cells. Thisobservation is consistent with recent work that shows that only afraction of the compounds that protect zebrafish neuromasts fromaminoglycosides and cisplatin also protect mammalian cochlear cells fromthese drugs (Ou et al. (2007) Hear. Res. 233: 46-53; Ou et al. (2010)Drug Discov. Today 15: 265-271; Vlasits et al. (2012) Hear. Res. 294:153-165).

TABLE 4 Cmpd. Zebrafish IC₅₀ Zebrafish LD₅₀ No. (μM) (μM) 1 No >5.0 2No >30 3 No <27 4 ~30 <90 5 No <0.6 7 No <1.0 8 No >50 9 No >50 12No >50 13 No >75

5. Protection Against Cisplatin-Induced Hair Cell Loss and Hearing Lossin Adult Mice Treated Locally Via Transtympanic Injection

Compound 4 was tested for protection against cisplatin-induced hair cellloss in vivo in adult mice (FIG. 5) after transtympanic injection.Either ear of the same FVB P28 wild-type mouse was trans-tympanicallyinjected (in a volume of 5 μL) with compound 4 (250 μM in 0.5% DMSO) or0.5% DMSO only, in a double-blinded manner. Two hours later, the micewere treated intraperitoneally (IP) with cisplatin 30 mg/kg body weight,which was expected to damage OHCs equally in both ears (FIG. 5A). At 14days post-cisplatin treatment, cochlear hair cells were analyzed byphalloidin staining. As expected, many OHCs at basal turns were lost inDMSO-treated ears; however, these OHCs were significantly protected inCompound 4 treated ears (paired t-tests, one-tailed or two-tailed) (FIG.5C-D). Without wishing to be bound by theory, these results indicatethat locally delivered compound 4 protects against cisplatin-inducedhair cell loss in vivo.

Referring to FIG. 5C-D, compound 4 protects against cisplatin-inducedhair cell loss in adult mice by local delivery in vivo. Either compound4 (250 μM) or DMSO was delivered to either ear of the same mouse for 2hrs; cisplatin was injected via i.p. and cochleae were fixed after 24hrs and analyzed (FIG. 5C). Confocal images of basal turn cochleae withphalloidin staining are shown for DMSO, compound 4, andcisplatin+compound 4 (FIG. 5C).

Referring to FIG. 5D, outer hair cell survival (%) in eleven mice isshown. Each line links two cochleae of each mouse. Using paired t-test,two-tailed: p=0.0028. Despite variations between animals, compound 4significantly protects cisplatin-induced hair cell loss in theseconditions. Referring to FIG. 5B, Compound 4 was tested for protectionagainst cisplatin-induced hearing loss in vivo in adult mice aftertranstympanic injection (TT), similar to the procedures described inFIG. 5A and FIG. 6A, followed by intraponeal injection of cisplatin (30mg/kg) in 2 hrs. Hearing tests (ABR) were performed 7 and 14 days posttreatment. Referring to FIG. 5B, hearing loss as measured by ABRthreshold shift (dB SPL) is significantly reduced at 16 and 32 kHz incompound 4 treated ears compared to DMSO control ears in 11 mice. (*:p<0.05, paired t-tests, two-sided).

6. Protection Against Noise-Induced Hearing Loss in Adult Mice TreatedLocally Via Transtympanic Injection

To confirm that compound 4 protects against noise-induced hearing lossin vivo, another set of experiments was performed (FIG. 6A). First,auditory brainstem response (ABR) thresholds were recorded at P28 inadult FVB wild-type mice and exposed to 100 dB SPL 8-16 kHz octave bandnoise for 2 hrs. A few minutes afterward, compound 4 (250 μM in 0.5%DMSO) or 0.5% DMSO only was injected (5 μL, trans-tympanically) ineither ear of the same mouse. Next, ABR thresholds were recorded 7 and14 days post-exposure and cochlear morphology was analyzed after theday-14 ABR measurement (FIG. 6A). The entire experiment was performed ina double-blinded manner.

Referring to FIG. 6A, an experimental design in which adult FVB mice atP28 were exposed to noise or TBI. Immediately afterward, compound 4 (250μM) or DMSO was delivered (via trans-tympanic injection) to either earof the same mouse. ABR and DPOAE thresholds were recorded prior, 7 days,or 14 days post noise exposure. Cochlear histology was examined at 14days.

Referring to FIG. 6A, a double-blinded design for compound versus DMSOinjection to either ear of the same mouse is shown.

The results in a total of 19-20 mice indicated that compound 4significantly protects adult mice from NIHL 7 days after exposure to 8kHz and 14 days after exposure 8 kHz and 16 kHz of noise (FIG. 6B andFIG. 6C). The mice had a mean of ˜12 dB of hearing protection at thesefrequencies. Moreover, significant differences were detected in amultiple regression longitudinal modeling with time points (pre-, D7 andD14) and frequencies (8, 16 and 32 kHz) as explanatory factors (p<0.01,t test of regression coefficients) (not shown). The wave 1 amplitudes ofABR at 16 kHz were also increased in compound 4 injected ears relativeto DMSO-injected ears (FIG. 6C). Without wishing to be bound by theory,these results suggest that compound 4 protects in vivo against NIHL whendelivered locally.

Referring to FIG. 6B, the ABR threshold shift at post-exposure day 14(D14) in DMSO and compound 4 treated ears in 19 mice is shown. Errorbars: S.E. **p<0.01;*p<0.05, paired t-test, two-tailed.

Box plots of the intra-mouse ABR threshold difference between the twotreated ears (ABR₄-ABR_(DMSO)) of each mouse is shown at pre- andpost-exposure day 7 (D7) and 14 (D14) in 20, 20, and 19 mice,respectively, at 8, 16, and 32 kHz. Significant differences wereobserved at 8 kHz at D7 and D14 and at 16 kHz at D14. **p<0.01 (pairedt-test). Additionally, significant differences were detected in multipleregression longitudinal modeling with time points (pre-, D7, and D14)and frequencies (8, 16, and 32 kHz) as explanatory factors (p<0.01,t-test of regression coefficients).

7. Effect of Compound 4 on Cisplatin Anti-Tumor Activity

Compound 4 did not interfere with cisplatin anti-tumor activity in threetumor cell lines (two mouse medulloblastoma neurosphere cell lines andone human neuroblastoma cell line) although it did so to certain extentin three other tumor cell lines (two medulloblastoma neurosphere celllines and one human neuroblastoma cell line) (Morfouace, M. et al.Cancer cell 25, 516-529, 2014). FIG. 11 provides strong evidence thatour compound 4 is more suitable for local delivery while compounds 7 and12 exhibited no interference in all tumor cell lines (except one forCompound 7) and therefore were better suitable for both systemic andlocal delivery.

J. Prophetic Examples

1. Protection Against Cisplatin Ototoxicity Ex Vivo in Neonatal MouseCochlear Explant Culture

The ability of the top 18 compound hits to protect against cisplatinototoxicity will be measured in wild-type mouse cochleae harvested fromP3 mice and grown in medium for 1-4 days at 37° C. The explants will beisolated and grown with the aid of matrigel (Driver and Kelley (2010)Curr. Protoc. Neurosci. Chapter 4, Unit 4 34: 31-10). Cisplatin solutionwill be added in a final concentration of 50 μM, 1 day after cochleaeare placed in medium. For every compound tested, hair cell death will becompared under four conditions: growth medium only, 50 μM cisplatinonly, test compound only, and test compound with 50 μM cisplatin. Eachcompound will be tested at least three concentrations (IC₁₀, IC₅₀, andIC₉₀) based on the dose responses in the HEI-OC1 cell experiments. Inaddition, each compound's toxicity will be tested at three or moreconcentrations (1×IC₉₀, 5×IC₉₀, and 25×IC₉₀). Each compound's IC₅₀(potency of protection) and LD₅₀ (toxicity) will be estimated inexplants.

After immunostaining with phalloidin, both outer and inner hair cells inthe cultured cochleae will be counted after each treatment by confocalmicroscopy. Co-immunostaining with Myo7a will further confirm that thephalloidin+ cells are viable hair cells. The live hair cells will beenumerated in two separate 160 m long areas in the cochlear apical,middle, and basal regions, respectively.

Two-sample two-sided t test will be applied to compare the percentage ofsurviving cells between cells treated by Cisplatin-only (control) vs.cisplatin-plus-compound at a given concentration. Five cochleae will betested at each concentration of each compound, to adjust for thevariability in ex-vivo explant cultures. zVAD-fmk and pifithrin-a willbe used as positive control at concentrations reported to confercisplatin protection in mouse cochlear explants (Atar and Avraham (2010)Neuroscience 168: 851-857; Liu et al. (1998) Neuroreport 9: 2609-2614;Zhang et al. (2003) Neuroscience 120: 191-205).

2. Protection Against Noise- and Blast Injury-Induced Hearing Loss InVivo in Adult Mouse Models

The protective effects of the top 4 compounds, administered locally(transtympanic injection into the middle ear), will be tested againstNIHL and blast injury-induced hearing loss in adult mouse models. Thelocal delivery route was chosen for several reasons. First, it isfrequently used in mammalian hearing studies, as it offers minimalinvasiveness and simple procedures. In fact, drugs are commonlyadministered via this route by pediatricians and ENT doctors to patientsof diverse ages (Banerjee and Pames (2005) Otol. Neurotol. 26: 878-881;Dodson et al. (2004) Ear Nose Throat J. 83: 394-398; McCall et al.(2010) Ear Hear. 31: 156-165; Muller and Barr-Gillespie (2015) Nat. Rev.Drug Discov. 14: 346-365; Rauch (2004) Otolaryngol. Clin. North Am. 37:1061-1074). If the compounds work well in murine models when deliveredin this manner, they can be directly tested for prevention ofcisplatin-associated hearing loss in patients undergoing cisplatinchemotherapy in clinical trials. Second, transtympanic delivery allowsthe compounds to diffuse easily across the round window membrane intothe endolymphatic fluid (Borkholder (2008) Curr. Opin. Otolaryngol. HeadNeck Surg. 16: 472-477; Mizutari et al. (2013) Neuron 77: 58-69; Swan etal. (2008) Adv. Drug Deliv. Rev. 60: 1583-1599; Tamura et al. (2005)Laryngoscope 115: 2000-2005), such that their potency and toxicity canbe directly tested in vivo with little concern about the blood-labyrinthbarrier (BLB). In the future oral and other routes may be considered forfurther characterization of in vivo properties of these compounds (e.g.,solubility, permeability, pharmacokinetics/pharmacodynamics (PK/PD), andabsorption, distribution, metabolism, excretion, and toxicology(ADMET)).

The compounds to test in this manner will be chosen on the basis of thefollowing considerations: (1) they exhibit potent IC₅₀ values andminimal toxicity (i.e., high LD₅₀/IC₅₀ values, preferably >50-100 μM);(2) they target several different biological targets/pathways; and (3)they can be delivered via other routes (e.g., oral).

For tests of noise injury, wild-type FVB mice will be used at age P28,when hearing has matured but long before significant age-related hearingloss (Kermany et al. (2006) Hear Res. 220: 76-86; Maison et al. (2002)J. Neurosci. 22: 10838-10846; Maison et al. (2007) J. Neurophysiol. 97:2930-2936; Zheng et al. (1999) Hearing Research 130: 94-107). Thestandard noise exposure protocols (94, 100, 106, 116, and 120 dB soundpressure level (SPL) ocaave-band 8-16 kHz noise for 2 hrs) havepreviously been tested in various transgenic mouse strains from the FVBbackground (Maison et al. (2002) J. Neurosci. 22: 10838-10846; Maison etal. (2007) J Neurophysiol. 97: 2930-2936). These noise injury protocolsled to hearing loss (ABR) (see FIG. 6A-D) similar to those previouslyreported in CBA/CaJ mice (Wang et al. (2002) J. Assoc. Res. Otolaryngol.3: 248-268).

Repeated impulses at 135-155 dB SPL can effectively recapitulate theeffects of blast injury in adult mouse cochleae. Previous studies ofblast injuries in animal models have demonstrated that 50-160 repeatedimpulses at 147-160 dB SPL impose physiological and morphological damageto the cochleae of chinchilla, sheep and pigs similar to 3-4 impulses of14 psi blasts (194 peak dB SPL) in rats (Choi et al. (2008) Free Radic.Biol. Med. 44: 1772-1784; Hamemik et al. (1987) J. Acoust. Soc. Am. 81:1118-1129; Henselman et al. (1994) Hear. Res. 78: 1-10; Kopke et al.(2005) Acta Otolaryngol. 125: 235-243; Roberto et al. (1989) Ann. Otol.Rhinol. Laryngol. Suppl. 140: 23-34). More interestingly, 3-4 impulsesof 14 psi blasts caused 43% OHC loss and 30-40 dB ABR thresholdelevation in rats 21 days post-blast, damage that resembles that causedby 6 hrs of continuous exposure to 105 dB SPL octave-band noise centeredat 4 kHz in chinchillas (Choi et al. (2008) Free Radic. Biol. Med. 44:1772-1784; Ewert et al. (2012) Hear. Res. 285: 29-39; Kopke et al.(2005) Acta Otolaryngol. 125: 235-243). Based on these results, a rangeof 135-155 dB SPL octave-band 8-16 kHz noise impulses of ˜10-ms durationwere chosen, which can be repeated 100 times at 1−s intervals in mousemodels to mimic traumatic blast injury (Choi et al. (2008) Free Radic.Biol. Med. 44: 1772-1784; Ewert et al. (2012) Hear. Res. 285: 29-39;Henselman et al. (1994) Hear. Res. 78: 1-10; McFadden et al. (2000) J.Acoust. Soc. Am. 107: 2162-2168).

FIG. 6A depicts the experimental design. Mice exposed to noise or blastexposure will be immediately treated with the individual compounds inone ear and vehicle control (0.5% DMSO) in the other ear. DMSO orcompound will be delivered locally at the highest feasible dose (whichshould be much higher than the IC₅₀ in cochlear explants but not toxicby itself in vivo) by trans-tympanic injection into the adult mousemiddle ear at ˜5 μL per ear. The ABR and Distortion Products OtoacousticEmissions (DPOAE) will be measured pre-noise exposure or TBI and at 1and 2 weeks post-injection. After hearing tests by ABR and DPOAE, themice will be cardiac-perfused for fixation and harvesting of thecochleae. The cochleae will be analyzed by using both whole-mountpreparations and sections, and immunofluorescence will be used to detectHC/SC markers (i.e., phalloidin, Myo7a, Prestin, and Sox2, etc.) andsynaptic markers (Ctbp2, GluR2/3 and Tuj1) (Liu et al. (2014) PLoS One9: e89377).

The entire procedure will be double-blinded: one person will encode DMSOor compound while the other person will randomly inject the left andright ears of the same mouse, and the person who records ABR and DPOAEwill not know which ear was injected with compound until the entireexperiment is completed.

a. ABR/DPOAE Measurements in Adult Mice

ABR measurements have been previously described in detail (Dallos et al.(2008) Neuron 58: 333-339; Gao et al. (2007) Mol. Cell Biol. 27:4500-4512; Liberman et al. (2002) Nature 419: 300-304; Liu et al. (2014)PLoS One 9: e89377; Wu et al. (2004) Brain Res. Mol. Brain Res. 126:30-37; Yamashita et al. (2012) PLoS One 7: e45453). Briefly, mice willbe anesthetized by intraperitoneal injection of Avertin (0.5 mg/kg bodyweight) and placed on an electric heating pad to maintain bodytemperature, using a homeothermic blanket system (Harvard ApparatusLtd). Mice that die or show signs of middle-ear dysfunction during thecourse of the experiment will be excluded from analysis. All recordingswill be conducted in a sound booth (Industrial Acoustic Company). Foracoustic stimulation and measurements two speakers (f1 and J2; EC1) anda microphone (ER-10B, Etymotic Research, Elk Grove Village, Ill.) areconnected to a short flexible coupler tube with a tapered plastic tipthat is inserted into the external auditory meatus. The microphone willbe calibrated in situ, with the coupler in the measuring position. Atfrequencies higher than 22 kHz, the frequency responses of themeasurement microphone (ER10B+) are lower than those of a referencemicrophone (ACO-7017; ACO Pacific, Inc., Belmont, Calif.). Therefore,DPOAE 2f1−f2 responses will be recorded at a frequency f1 range of5454-18180 Hz, using the TDT BioSig III system (TDT). Signal duration is83.88 ms, with a repetition rate of 11.92/s. The f1 and J2 responses arepassed separately through an RX6 MultiFunction Processor (TDT) fordigital/analog conversion to PA5 programmable attenuators. Stimulusintensity will be reduced from 90 to 0 dB in 5 dB steps to establishthresholds and will be digitally sampled at 200 kHz and averaged from100 discrete spectra. The signals are delivered through ED1 speakerdrivers that feed into the EC1 electrostatic speakers coupled to the earcanal. The resulting ear canal sound pressure will be recorded with anER10B+ low noise microphone (gain 0×) and probe (Etymotic) housed in thesame coupler as thefl and J2 speakers. The output of the ER10B+amplifier is routed directly to an RX6 MultiFunction Processor (TDT) foranalog/digital conversion for sampling at 200 kHz. Fast-Fouriertransforms (FFT) of averaged responses will be generated by using TDTBioSigRP software on the resultant waveform (TDT). Noise floors will bedetermined by averaging the sound levels of 10 frequency bins above andbelow the 2f1−f2 frequency bin. No instrumental distortion products havebeen observed in evaluation of ears postmortem.

b. Noise Injury in Adult Mice

Mice will be placed individually in a cage within a custom-made acrylicchamber in which no two sides are parallel. The sound stimulus will beproduced by an RZ6 processor (Tucker-Davis Technologies, GainesvilleFla.), filtered (Frequency Devices, Inc., Haverhill, Mass.), amplified(Crown XTi 1000 amplifier; Crown, Elkhart, Ind.), and delivered to theacrylic chamber via a speaker horn (JBL, Northridge, Calif.). The soundpressure level will be measured through a ¼-inch freefield microphone(ACO Pacific, Belmont, Calif.) and calibrated to a 124 dB pistonphone(Bruel and Kjaer, Denmark). Prior to experimental noise exposure, fourquadrants of the chamber will be sampled with the ¼-inch microphone toensure that sound pressure varies by <0.5 dB across the measuredpositions.

c. Trans-Tymipanic Injection of Adult Mice

Mice will be anesthetized by intraperitoneal (i.p.) injection of Avertinor ketamine and xylazine. Body temperature is maintained on a heatingpad during the surgical procedure. Lubricant eye ointment is applied toprevent corneal ulcers, as the blinking reflex disappears duringsurgery. The tympanic membrane is visualized with a surgicalstereomicroscope. Using a 33-gauge cannula, 5 μL of compound or DMSO inPBS is gently injected through the tympanic membrane, followed bysurgical stereomicroscopic confirmation that the solution is in themiddle ear cavity. Mice are then placed in the cage on the heating padfor an additional 30 minutes. After surgery, all mice are allowed torecover on a heating pad before being returned to the animal housingfacility.

K. References

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It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A method of treating hearing impairment, themethod comprising administering to a subject diagnosed with a need fortreatment of hearing impairment a therapeutically effective amount of acyclin-dependent kinase 2 (CDK2) inhibitor, or a pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1, wherein the CDK2inhibitor is selected from a paullone derivative, a purine derivative,and a 3-(2-phenylhydrazono)indolin-2-one derivative, or apharmaceutically acceptable salt thereof.
 3. The method of claim 2,wherein the CDK2 inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 2,wherein the CDK2 inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the CDK2 inhibitor is administered in an amount of from about0.001 μM to about 1.0×10⁴ μM at least once every three weeks.
 6. Themethod of claim 1, wherein the hearing impairment is drug-induced. 7.The method of claim 6, wherein the drug is a chemotherapeutic agent. 8.The method of claim 6, wherein the drug is an antibiotic.
 9. The methodof claim 9, wherein the antibiotic is selected from daunorubicin,doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin,mitomycin-C, amikacin, apramycin, arbekacin, astromicin, bekanamycin,dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin,neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin,sisomicin, spectinomycin, streptomycin, tobramycin, and verdamicin, or apharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a CDK2 inhibitor, wherein the CDK2 inhibitor isnot a paullone derivative, or a pharmaceutically acceptable saltthereof; and one or more of: a) at least one agent known to treathearing impairment, or a pharmaceutically acceptable salt thereof; andb) at least one agent known to prevent hearing impairment, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 11. The composition of claim 10, wherein the CDK2inhibitor has a structure represented by a formula:

wherein each of R^(5a) and R^(5b) is independently selected fromhydrogen, C1-C8 alkyl, (CH₂)_(q)R⁸, and C═O(CH₂)_(q)R⁸ and wherein eachof R^(5a) and R^(5b) is independently substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl; wherein q, when present, is an integer selected from1, 2, 3, and 4; wherein R⁸, when present, is selected from hydrogen,—OH, —SH, —NH₂, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, andC1-C4 dialkylamino; wherein R⁶ is selected from halogen, OR⁹, andNR^(10a)R^(10b); wherein R⁹, when present, is selected from C1-C8 alkyl,(CH₂)_(p)Cy¹, and (CH₂)_(p)Ar¹ and wherein R⁹, when present, issubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl; wherein p, when present,is an integer selected from 0, 1, 2, and 3; wherein Cy¹, when present,is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;wherein Ar¹, when present, is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;wherein each of R^(10a) and R^(10b), when present, is independentlyselected from C1-C8 alkyl, Cy², Ar², (CH₂)_(r)Cy², and (CH₂)_(r)Ar² andsubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl; wherein r, when present,is an integer selected from 0, 1, 2, and 3; wherein Cy², when present,is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;wherein Ar², when present, is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —OH, —CN, —NO₂, —NH₂, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; andwherein R⁷, when present, is selected from hydrogen and C1-C8 alkyl, ora pharmaceutically acceptable salt thereof.
 12. The composition of claim10, wherein the CDK2 inhibitor has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.
 13. The composition ofclaim 10, wherein the 3 CDK2 inhibitor has a structure represented by aformula:

wherein each of R^(11a), R^(11b), R^(11c), and R^(11d) is independentlyselected from hydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4dialkylamino, —SO₂R¹⁵, and —CO₂R¹⁵; wherein each occurrence of R¹⁵, whenpresent, is independently selected from hydrogen, —CH₃, —CFH₂, —CF₂H,—CF₃, —NH₂, —NH(CH₃), and —N(CH₃)₂; wherein each of R¹² and R¹³ isindependently selected from hydrogen and C1-C4 alkyl; wherein each ofR^(14a), R^(14b), R^(14c), R^(14d), and R^(14e) is independentlyselected from hydrogen, halogen, —OH, —SH, —CN, —NO₂, —NH₂, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4dialkylamino, —SO₂R¹⁶ and —CO₂R¹⁶; and wherein each occurrence of R¹⁶,when present, is independently selected from hydrogen, —CH₃, —CFH₂,—CF₂H, —CF₃, —NH₂, —NH(CH₃), and —N(CH₃)₂, or a pharmaceuticallyacceptable salt thereof.
 14. The composition of claim 10, wherein theCDK2 inhibitor has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.
 15. The composition ofclaim 10, wherein the CDK2 inhibitor has a structure represented by aformula:

wherein R²⁰ is selected from —SO₂R^(20a), —OH, NH₂, substituted amide,C1-C4 alkyl carbonyl, C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl,and C1-C8 alkyl and is substituted with 0, 1, or 2 groups independentlyselected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl;wherein each of R²¹, R²³, and R²⁵ is independently selected fromhydrogen, halogen, —OH, NH₂, C1-C4 monoalkylamino, C1-C4dialkylaminomethyl, and C1-C8 alkyl and is independently substitutedwith 0, 1, or 2 groups independently selected from halogen, —OH, —CN,—NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy,C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein each of R²²and R²⁴ is independently selected from hydrogen and C1-C8 alkyl and isindependently substituted with 0, 1, or 2 groups independently selectedfrom halogen, —OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl, or apharmaceutically acceptable salt thereof.
 16. The composition of claim10, wherein the CDK2 inhibitor has a structure represented by a formula:

wherein each occurrence of X is independently a halogen; wherein each ofR³⁰, R³¹, R³², and R³³ is independently selected from hydrogen and C1-C8alkyl and is independently substituted with 0, 1, or 2 groupsindependently selected from halogen, —OH, —CN, —NO₂, —NH₂, C1-C4monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4dialkylaminomethyl; and wherein R³⁴ is selected from —OH, NH₂, C1-C4monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and issubstituted with 0, 1, or 2 groups independently selected from halogen,—OH, —CN, —NO₂, —NH₂, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4monoalkylamino, and C1-C4 dialkylaminomethyl, or a pharmaceuticallyacceptable salt thereof.
 17. The composition of claim 10, wherein theCDK2 inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.
 18. The composition ofclaim 10, wherein the CDK2 inhibitor is selected from:

or a pharmaceutically acceptable salt thereof.
 19. The composition ofclaim 10, wherein the pharmaceutical composition is used to treathearing impairment.
 20. The composition of claim 10, wherein thepharmaceutical composition is used to prevent hearing impairment.